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Publication numberUS20030186283 A1
Publication typeApplication
Application numberUS 10/332,795
Publication dateOct 2, 2003
Filing dateJul 11, 2001
Priority dateJul 11, 2000
Also published asEP1299725A2, US6946253, WO2002004492A2, WO2002004492A3
Publication number10332795, 332795, US 2003/0186283 A1, US 2003/186283 A1, US 20030186283 A1, US 20030186283A1, US 2003186283 A1, US 2003186283A1, US-A1-20030186283, US-A1-2003186283, US2003/0186283A1, US2003/186283A1, US20030186283 A1, US20030186283A1, US2003186283 A1, US2003186283A1
InventorsJohn Clements, Alasdair Maclean
Original AssigneeClements John Barklie, Maclean Alasdair Roderick
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Azodicarbonamide ejects zinc bound to protein; solid phase synthesis; nuclear magnetic resonance
US 20030186283 A1
Abstract
The present invention relates to a method for detecting an agent for use in the treatment of herpes virus infection and use of known agents, such as 2,2′-dithiobisbenzamide (DIBA) and azodicarbonamide (ADA), and unknown agents, which selectively eject zinc bound to a zinc finger protein, for the manufacture of a medicament for the treatment of herpesvirus infections.
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Claims(34)
1. A method for detecting an agent for use in the treatment of herpes virus infection comprising the steps of:
(a) forming a herpes virus polypeptide/zinc complex;
(b) adding a test agent to said polypeptide/zinc complex; and
(c) detecting any change in the polypeptide/zinc complex.
2. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 1 wherein the agent is a chemical, nucleic acid analogue, peptide and/or protein.
3. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 2 wherein the agent is a C-nitroso and related compound such as 6-nitroso 1,2-benzopyrone (NOBP), 2-nitrosobenzamide, 3-nitrosobenzamide (NOBA), 4-nitrosobenzamide, 5-nitroso-1(2H)-isoquinolinone (5-NOQ), 7-nitroso-1(2H) isoquinolin (5-NOQ), 8-nitroso-1(2H)-isoquinolinone (8-NOQ), and related compounds including nicotinamides, pthalhydrazides and 1,3-benzoxazine-2,4 diones; phenylthiols; dithiaheterocyclic molecules; disulphide benzamides or azoic compounds.
4. A method of detecting an agent for use in the treatment of herpes virus infections according to claim 3 wherein said disulphide benzamide compound is 2,2′-dithiobisbenzamide (DIBA) and said azoic compound is azodicarbonamide (ADA).
5. A method for detecting an agent for use in the treatment of herpes virus infection according to any one of claims 1 to 4 wherein the polypeptide is herpes virus HSV-1 or HSV-2 IE63 protein as shown in FIG. 1 or functional homologue thereof.
6. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 5 wherein the polypeptide is VZV ORF4, HCMV UL69, Epstein-Barr virus BMLF1 (SM/MTA), HHV-6 U42, HHV-7 U42, HHV-8 ORF5.7, equine herpes virus-1 ORF3, equine herpes virus-4 ORF3, bovine herpes virus-1 BICP27, pseudorabies virus UL54, Marek's disease virus UL54, murine cytomegalovirus M69, herpes virus saimiri ORF57, bovine herpes virus-4 ORF57, avian herpes virus-1 ORF57 and murine herpes virus-68 ORF57 as shown in FIG. 1 or functional derivatives or functional homologues thereof.
7. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 6 wherein the polypeptide comprises at least the C-terminal regions of IE63 and its homologues as shown in FIG. 2.
8. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 7 wherein the polypeptide comprises the zinc finger motifs of IE63 homologues of the alpha-, beta- or gammaherpesvirus family as highlighted in bold in FIG. 2.
9. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 8 wherein said zinc finger motifs comprise at least the Cys-X10-His-X3-Cys-X4-Cys-X14-His-X6-Cys alphaherpesvirus subfamily zinc-finger motif, or Cys-X12-His-X1-Cys-X4-Cys-X17-Cys betaherpesvirus subfamily zinc-finger motif or His-X3-Cys-X4-Cys gammaherpesvirus subfamily zinc finger motif of herpes virus IE63 functional homologues.
10. A method for detecting an agent for use in the treatment of herpes virus infection comprising the steps of;
a) forming a herpes virus polypeptide/zinc complex wherein said polypeptide comprises at least the Cys-X10-His-X3-Cys-X4-Cys-X14-His-X6-Cys alphaherpesvirus subfamily zinc-finger motif, or Cys-X12-His-X1-Cys-X4-Cys-X17-Cys betaherpesvirus subfamily zinc-finger motif or His-X3-Cys-X4-Cys gammaherpesvirus subfamily zinc finger motif of herpes virus IE63 functional homologues;
b) adding a test agent to said polypeptide/zinc complex; and
c) detecting any change in the polypeptide/zinc complex.
11. A method for detecting an agent for use in the treatment of herpes virus infection according to any preceding claim wherein said zinc is provided in the form of a standard dialysis buffer comprising a known concentration of zinc.
12. A method for detecting an agent for use in the treatment of herpes virus infection according to any preceding claim wherein detection of said agent is based on a change in the properties of said polypeptidelzinc complex.
13. A method for detecting an agent for use in the treatment of herpes virus infection according to any preceding claim wherein said properties are measured by standard amino acid analysis and atomic adsorption spectroscopy.
14. A method for detecting an agent for use in the treatment of herpes virus infection according to any preceding claim wherein detection of any change in the properties of said polypeptide/zinc complex is a measure of the test agent's ability to eject zinc and destabilise viral zinc fingers.
15. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 14 wherein detection of any change in the properties of said polypeptide/zinc complex is achieved by using 65Zn2+ or NMR.
16. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 15 wherein detection of any change in the properties of said polypeptide/zinc complex is achieved by using spectrofluorimetry with stop flow facilities.
17. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 16 wherein said spectrofluorimetry utilises several fluorescent indicators, which exhibit an increase in fluorescence upon binding of zinc.
18. A method for detecting an agent for use in the treatment of herpes virus infection according to claim 17 wherein said fluorescent indicators include Newport Green™ or N-(6-methyoxy-8-quinolyl)-p-toluenesulphonamide.
19. A method for detecting an agent for use in the treatment of herpes virus infection according to claims 17 and 18 wherein said fluorescent indicators are used to examine zinc binding, strength of zinc binding and the effect of said test agents on said polypeptide/zinc complex.
20. A kit for diagnostic in vitro detection of agents for use in the treatment of herpes virus infection, wherein the kit comprises:
a) a herpes virus polypeptide, said polypeptide comprising a sequence selected from the group consisting of (at least) the Cys-X10-His-X3-Cys-X4-Cys-X14-His-X6-Cys alphaherpesvirus subfamily zinc-finger motif, Cys-X12-His-X1-Cys-X4-Cys-X17-Cys betaherpesvirus subfamily zinc-finger motif and His-X3-Cys-X4-Cys gammaherpesvirus subfamily zinc finger motif of herpes virus IE63 functional homologues;
b) a source of zinc, in order that when added to said polypeptide, a polypeptide/zinc complex is formed; and
c) means for enabling determination of any change in said polypeptide/zinc complex in the presence of an agent.
21. A kit for diagnostic in vitro detection of agents for use in the treatment of herpes virus infection according to claim 20 wherein the polypeptide and zinc are provided as a preformed polypeptide/zinc complex.
22. A kit for diagnostic in vitro detection of agents for use in the treatment of herpes virus infection according to claim 21 wherein detection of said agent is based on a change in the properties of said polypeptide/zinc complex.
23. A kit for diagnostic in vitro detection of agents for use in the treatment of herpes virus infection according to claim 22 wherein detection of any change in the properties of said polypeptide/zinc complex is a measure of the test agent's ability to eject zinc and destabilise viral zinc fingers.
24. A kit for diagnostic in vitro detection of agents for use in the treatment of herpes virus infection according to claim 23 wherein detection of any change in the properties of said polypeptide/zinc complex is achieved by using 65Zn2+ or NMR.
25. A kit for diagnostic in vitro detection of agents for use in the treatment of herpes virus infection according to any one of claims 20 to 24 wherein said polypeptide or polypeptide/zinc complex is immobilised on a solid substrate.
26. A kit for diagnostic in vitro detection of agents for use in the treatment of herpes virus infection according to claim 25 wherein said solid substrate is a microtiter plate, cuvette or nitrocellulose.
27. A pharmaceutical composition comprising an agent obtained by the method according to any one of claims 1 to 20 or any synthetic functional derivative thereof together with a pharmaceutically acceptable carrier thereof for use in treating herpes virus infections.
28. An antiherpesvirus agent detected by the method according to claims 1 to 20.
29. A pharmaceutical composition comprising the antiherpesvirus agent according to claim 28.
30. A pharmaceutical composition according to claim 29 in conjunction with a further known antiherpesvirus agent together with a pharmaceutically acceptable carrier thereof.
31. Use of previously identified antiretroviral agents for the manufacture of a medicament for the treatment or prophylaxis of herpes virus infections wherein said antiretroviral agents were identified previously as effective in their treatment of retroviruses only due to their action of Zn-ejection from the zinc finger motif of HIV-1 NCp7.
32. Use of previously identified antiretroviral agents according to claims 30 and 31 wherein said antiretroviral agents are C-nitroso and related compounds or disulphide benzamide and azoic compounds.
33. Use of previously identified antiretroviral agents according to claims 30 to 32 wherein said disulphide benzamide compound is 2,2′-dithiobisbenzamide (DIBA) and said azoic compound is azodicarbonamide (ADA).
34. Use of IE63 polypeptide, functional derivative or functional homologue thereof in a method according to any one of claims 1 to 20.
Description

[0001] The present invention relates to a method for detecting an agent for use in the treatment of herpes virus infection and use of known and unknown agents for the manufacture of a medicament for the treatment of herpesvirus infections.

[0002] A paradigm for the development of antivirals was based on the identification of agents that selectively eject zinc from retroviral zinc finger proteins. One such protein is the human immunodeficiency HIV-1 nucleocapsid protein NCp7, which is essential for early and late virus replication. NCp7 interacts with the viral RNA at a packaging site (1). This 55bp amino acid protein contains two zinc fingers, one of which is highly conserved among the retroviruses (reviewed in 2). The NCp7 CCHC zinc finger represents a rare conserved feature, absent in cellular proteins, against the extreme variation of other retrovirus components which suggests that mutation to resistance against reagents that target conserved zinc finger motifs may be difficult to achieve. Potent anti-HIV-1 agents that selectively target the NCp7 protein zinc finger by ejecting zinc have been identified which are non-toxic to cells (3,4).

[0003] The following summarised documents describe the use and action of such agents in the treatment of retroviral infections:

[0004] Huang et al. 1998 describe agents that target retroviral nucleocapsid protein zinc fingers without seriously affecting cellular zinc finger proteins. Specifically, the agents are 3-nitrosobenzamide (NOBA), disulfide benzamides (DIBAs or 2,2′-dithiobisbenzamides), dithiaheterocyclic molecules such as 1,2-dithiane-4,5-diol, 1,1-dioxide, cis(dithiane), α-carbonyl azoic compounds such as azodicarbonamide (ADA), and others. However, this document only discloses the agents' action on retroviruses and in particular nucleocapsid p7 (NCp7).

[0005] Vandervelde et al 1996 describe the anti-HIV-1 properties and clinical/pre-clinical data of 1,1′-azobisformamide (ADA), indicating toxicity studies of the compound in patients.

[0006] U.S. Pat. No. 5,516,941 describes c-nitroso compounds which destabilise zinc fingers such as 6-nitroso 1,2-benzopyrone (NOBP), 2-nitrbsobenzamide, 3-nitrosobenzamide (NOBA), 4-nitrosobenzamide, 5-nitroso-1(2H)-isoquinolinone (5-NOQ), 7-nitroso-1(2H)isoquinolin (5-NOQ), 8-nitroso-1(2H)-isoquinolinone (8-NOQ), and related compounds including nicotinamides, pthalhydraziides and 1,3-benzoxazine-2,4 diones for inactivating retroviruses either alone or in combinations thereof. It also provides for methods of detecting compounds that can inactivate retroviruses by testing for the effect of zinc finger destabilising i.e. ejection of zinc measured using NMR.

[0007] U.S. Pat. No. 5,463,122 and its divisional application U.S. Pat No. 5,668,178 describe the preparation and use of phenylthiols and dithiobisbenzamides in the treatment of retrovirus infections including HIV treatment.

[0008] U.S. Pat No. 5,585,367 describe the use of azoic compounds (including ADA) in the treatment of retroviral infections. It also details clinical studies on the use of ADA but at no time does the article refer to the drug's use in the treatment of viruses other than retroviruses.

[0009] In summary, although some of these documents detail the use and action of specific drugs in the treatment of retroviral infection at no time is it inferred that such drugs can be used in the treatment of non-retrovirus infections such as herpesvirus infections.

[0010] Herpesviruses are one of the most important virus families and cause a range of prominent medical or veterinary diseases. Eight different herpesviruses whose natural host is man have been identified so far: herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), Epstein-Barr virus, human cytomegalovirus (HCMV) and human herpesvirus (HHV) types 6-8 (reviewed in 5). A large proportion of people world-wide have been exposed to, and may be latently infected with, one or more herpesviruses. Whereas in general an intact immune system keeps these viruses in check, immunocompromised individuals are particularly at risk. HCMV disease in graft recipients, newborns and immunocompromised patients accounts for considerable morbidity. VZV can be a severe and life threatening problem for leukaemic children and patients undergoing chemotherapy or immunosuppressive drug treatment for organ transplants. Herpesviruses have been implicated in the aetiology of different types of cancer with the recently discovered gammaherpesvirus HHV-8 implicated in Kaposi's sarcoma, a major neoplasm of AIDS patients.

[0011] At present there are few antiviral agents of broad specificity against the herpesvirus family of viruses (6), and resistance to antiherpesvirus drugs such as acyclovir, against HSV and VZV, and gancyclovir, against HCMV, is an increasing problem (7,8,9), prompting the call for new therapeutic approaches to herpesvirus infections(7).

[0012] It is an object of the present invention to obviate and/or mitigate at least some of the above disadvantages.

[0013] Broadly speaking, the present invention is based on the present inventors' observation that the spacing and metal co-ordinating residues in the IE63 zinc finger of herpes simplex virus type I are conserved in all related homologues within the alphaherpesvirus sub-family. Similar conservation of spacing of zinc finger motifs but with different arrangements of the conserved motif residues was also discovered by the inventors within the betaherpesvirus and gammaherpesvirus family.

[0014] IE63 (also called ICP27) is an essential HSV-1 protein (reviewed in 10). An IE63 homologue exists in all examples of mammalian and avian herpesviruses sequenced so far (around twenty). IE63 is the only HSV-1 immediate early regulatory protein conserved in other herpesvirus indicative of its central role in viral gene regulation. The product of the HSV-1 and HSV-2 UL54 gene, IE63 (ICP27) has counterparts in other herpesviruses namely VZV ORF 4, HCMV UL69, Epstein-Barr virus BMLF1 (SM/MTA), HHV-6 U42, HHV-7 U42, HHV-8 ORF57, equine herpesvirus-1 ORF3, equine herpesvirus-4 ORF3, bovine herpesvirus-1 BICP27, pseudorabies virus UL54, Marek's disease virus UL54, murine cytomegalovirus M69, herpesvirus saimiri ORF57, bovine herpesvirus-4 ORF57, avian herpes virus-1 ORF57 and murine herpesvirus-68 ORP57. HSV-1 IE63 is an essential immediate-early phosphoprotein for the progression of the virus lytic replication cycle from immediate early to early and late stages, its functions affect the transcription of virus genes into RNA and subsequent post-transcriptional processing of this RNA. The action of IE63 is complex, binding other herpesvirus proteins, colocalising with splicing factors and binding RNA with a preference for viral intron-less transcripts (11-13) and inhibiting splicing of both viral and cellular transcripts (14). IE63 causes the nuclear retention of intron-containing transcripts while facilitating the nuclear export of viral intron-less transcripts allowing the virus to take control of host gene expression. The post-transcriptional action of IE63 is even more complex, enhancing 3′ RNA processing at late viral poly(A) sites and stabilising 3′ ends of mRNA.

[0015] IE63 is a zinc finger protein. The yeast genome encodes some 500 zinc finger proteins (reviewed in 11, 12) and estimates are that some 1% of all mammalian genes encode such motifs. The action of zinc fingers include binding to DNA, RNA and DNA-RNA hybrids as well as mediating protein-protein interactions. potentiating self interaction and interactions with other proteins. The IE63 zinc binding region itself (18) is required for self interaction (19, 20) and for interaction with CK2(19).

[0016] The discovery by the present inventors that the spacing and metal co-ordinating residues of the IE63 zinc finger and its homologues are conserved within each of the herpesvirus sub-families (alpha-, beta- and gammaherpesvirus; Example 1)is analogous to the retrovirus HIV-1 protein NCp7, which has been targeted for the development of antivirals that selectively eject zinc (reviewed in 2).

[0017] Inspection of the databases reveals that the three conserved zinc finger motifs within the alpha-, beta- and gammaherpesvirus families are divergent to any other identified zinc finger motif present in viral and cellular proteins. Thus, like HIV-1 Ncp7, the IE63 zinc finger represents a rare conserved feature, absent in cellular proteins, against the extreme variation of other virus, in this case herpesvirus, components. This discovery allows the development of new anti-herpes virus agents.

[0018] Thus, in a first aspect of the present invention there is provided a method for detecting an agent for use in the treatment of herpes virus infection comprising the steps of:

[0019] (a) forming a herpes virus polypeptide/zinc complex;

[0020] (b) adding a test agent to said polypeptide/zinc complex; and

[0021] (c) detecting any change in the polypeptide/zinc complex.

[0022] The method is particularly suited for the detection of agents which may serve as antiherpesvirus agents. The term antiherpesvirus agent is understood to mean an agent which when in contact with a herpesvirus and/or herpesvirus infected cells selectively kills and/or destabilises viruses from this virus family only. Killing or destabilising of herpesviruses may be achieved by, for example, interference of viral nucleic acid synthesis and/or regulation, virus-cell binding, virus uncoating or viral replication. Preferably, the action of the antiherpesvirus agent will not interfere unduly with the infected host cells' machinery.

[0023] The term agent is understood to include chemicals, nucleic acid analogues, peptides and/or proteins. For example, these may include C-nitroso and related compounds or disulpbide benzamides and azoic compounds such as 2,2′-dithiobisbenzamide (DIBA) and azodicarbonamide (ADA) respectively.

[0024] According to the present invention, the term polypeptide refers to herpesvirus HSV-1 and ESV-2 IE63 protein, and counterparts in other herpesviruses namely VZV ORF4, HCMV UL69, Epstein-Barr virus BMLF1 (SM/MTA), HHV-6 U42, HHV-7 U42, HHV-8 ORF57, equine herpesvirus-1 ORF3, equine herpesvirus-4 ORF3, bovine herpesvirus-1 BICP27, pseudorabies virus UL54, Marek's disease virus UL54, murine cytomegalovirus M69, herpesvirus saimiri ORF57, bovine herpesvirus-4 ORF57, avian herpes virus-1 ORF57 and murine herpesvirus-68 ORF57 as shown in FIG. 1, or functional derivatives or functional homologues thereof. In particular, it refers to a polypeptide comprising at least the C-terminal regions of IE63 and homologues as shown in FIG. 2. More particularly, it refers to polypeptides comprising the zinc finger motifs of IE63 homologues of the alpha-, beta- or gammaherpesvirus family as highlighted in bold in FIG. 2.

[0025] The term functional derivative thereof according to the present invention refers to any polypeptide containing at least the zinc finger motif of herpesvirus IE63 or its counterparts as shown in FIGS. 1 and 2. The skilled addressee will appreciate that it is possible to manipulate a full-length protein in order to express derivatives of the full-length polypeptide.

[0026] Furthermore, the term functional homologue refers to a polypeptide with a sequence similar to those depicted in FIGS. 1 and 2 with a conserved function.

[0027] It should be understood that the degree of similarity, over the full-length polypeptide, of functional homologues may vary greatly. That is, a functional homologue is defined by the conservation of amino acid residues in a motif required to characterise a protein family. Thus, there may be a low percentage of similarity of amino acid residues outwith a motif of interest in a full-length polypeptide but as long as said motif is conserved the protein maintains its function and is thus regarded as a functional homologue. In terms of the present invention, it can be seen from FIGS. 1 and 2 that a high percentage of similarity of amino acid residues in herpesvirus IE63 and its homologues is confined to the zinc-finger motif and there is a relative lack of conservation outwith this motif. In particular, functional honologues of IE63, according to the present invention are defined by the precise conservation of spacing and metal co-ordinating amino acid residues in the Zn-finger motif in each of the herpesvirus families. In more detail, Cys-X10-His-X3-Cys-X4-Cys-X14-His-X6-Cys in the alphaherpesvirus Zn-finger motif, Cys-X12-HiS-X4-Cys-X4-Cys-X17-Cys in the betaherpesvirus Zn-finger motif and His-X3-Cys-X4-Cys in the gammaherpesvirus subfamily Zn-finger motif of IE63 functional homologues.

[0028] In a further aspect of the present invention there is provided a method for detecting an agent for use in the treatment of herpes virus infection comprising the steps of:

[0029] a) forming a herpes virus polypeptide/zinc complex wherein said polypeptide comprises at least the Cys-X10-His-X3-Cys-X4-Cys-X14-His-X6-Cys alphaherpesvirus subfamily zinc-finger motif, or Cys-X12-His-X1-Cys-X4-Cys-X17-Cys betaherpesvirus subfamily zinc-finger motif or His-X3-Cys-X4-Cys gammaherpesvirus subfamily zinc finger motif of herpesvirus IE63 functional homologues;

[0030] b) adding a test agent to said polypeptide/zinc complex; and

[0031] c) detecting any change in the polypeptide/zinc complex.

[0032] In order to detect antiherpesvirus agents according to the present invention said polypeptide must first be complexed with zinc. Zinc may be provided in the form of a standard dialysis buffer comprising a known concentration of zinc.

[0033] Detection of said antiherpesvirus is based on a change in the properties of said polypeptide/zinc complex when a test agent is added. Said change will be a measure of the test agent's ability to eject zinc and destabilise viral zinc fingers. For example, displacement of zinc from said polypeptide/zinc complex is thus a measure of an agent's potential as an antiherpesvirus agent. It should be understood that the properties of said polypeptide/zinc complex such as concentration and zinc content of (purified) polypeptides may be measured by standard techniques such as standard amino acid analysis and atomic adsorption spectroscopy.

[0034] Detection of a change in said polypeptide/zinc complex may be achieved among other methods by using 65Zn2+ or NMR, which can detect ejection of zinc from said polypeptide/zinc complex by a test agent. For example, for the NCp7 zinc finger domain, loss of NMR signals due to a zinc bound histidine and the appearance of signals representing zinc-free histidine indicates ejection of zinc (21). Preferably, said detection uses spectrofluorimetry as applied to the NCp7 zinc finger (22) with stop flow facilities used to measure on/off rates for zinc binding. Detection of zinc using this method utilises several fluorescent indicators, which exhibit an increase in fluorescence upon binding of zinc. Said fluorescent indicators may, for example, be Newport Green™ or N-(6-methyoxy-8-quinolyl)-p-toluenesulphonamide (25). Thus, for example, said fluorescent indicators may be used to examine for zinc binding, strength of zinc binding and the effect of test agents on a polypeptide/zinc complex according to the present invention.

[0035] Generally speaking, any agents detected by the method according to the present invention that cause a change in said polypeptide/zinc complex may be used as an antiherpesvirus agent.

[0036] In a further aspect, the present invention also relates to use of an IE63 polypeptide, functional derivative or functional homologue thereof or polypeptide comprising a zinc finger motif as defined herein in the disclosed methods and use of a nucleic acid encoding said polypeptide, in the disclosed methods. Said polypeptide and its functional homologues or derivatives thereof are as described earlier Generally speaking, the skilled man will understand that the nucleic acid counterparts may be used for cloning, using standard techniques, nucleic acid constructs required for expression of said polypeptide or functional homologue thereof. Optionally, said nucleic acid may be used to clone the C-terminus encoding region of IE63 and its homologues, incorporating the conserved zinc finger motif according to the present invention. Furthermore, they may be used to express and purify said polypeptide. A method of purification of said polypeptide comprising a zinc finger motif can utilise the motif itself. For example, the dimerisation properties of a zinc finger motif can be utilised by binding said polypeptide to Glutathione beads, which are then used to purify further polypeptide from herpesvirus-infected cell extracts through self-interaction of the polypeptide. A further means of providing polypeptide is use of automated peptide synthesis.

[0037] In a third aspect, the present invention provides agents detected by the method according to the present invention and their use to treat herpesvirus infections. It should be understood that this may include any suitable pharmaceutical composition comprising, as active substance, any said agent and any synthetic functional derivative thereof. Such agents can also be used in conjunction with known antiherpesvirus agents in the treatment of herpes viral infections as well as, if necessary, one or more pharmaceutical adjuvants. This composition may be administered in any form by various means including topical application to the site of viral breakout eg. mouth for HSV-1 lytic cycle.

[0038] The discovery by the present inventors that the spacing and metal co-ordinating residues of the IE63 zinc finger and its homologues are conserved within each of the herpesvirus sub-families (alpha-, beta- and gammaherpesvirus; Example 1)is analogous to the retrovirus HIV-1 protein NCp7, which has been targeted for the development of antivirals that selectively eject zinc (reviewed in 2).

[0039] Thus, the present invention further provides the use of previously identified antiretroviral agents in the treatment of herpesvirus infection. Particularly, antiretroviral agents whose action is in the ejection of zinc bound to a zinc finger protein, for example, C-nitroso compounds such as 6-nitroso 1,2-benzopyrone (NOBP), 2-nitrosobenzamide, 3-nitrosobenzamide (NOBA), 4-nitrosobenzamide, 5-nitroso-1(2H)-isoquinolinone (5-NOQ), 7-nitroso-1(2H) isoquinolin (5-NOQ), 8-nitroso-1(2H)-isoquinolinone (8-NOQ), and related compounds including nicotinamides, pthalhydrazides and 1,3-benzoxazine-2,4 diones; phenylthiols; dithiaheterocyclic molecules; disulphide benzamides or azoic compounds. Preferred antiretroviral agents for use according to the present invention are the disulphide benzamide 2,2′-dithiobisbenzamide (DIBA) and azoic compound, azodicarbonamide (ADA). Said antiretroviral agents were identified previously as effective in the treatment of retroviruses only due to their action of Zn-ejection from the zinc finger motif of HIV-1 NCp7.

[0040] In a further aspect, the present invention provides the use of such previously identified antiretroviral agents for the manufacture of a medicament for the treatment or prophylaxis of herpes virus infections.

[0041] In a yet further aspect there is provided a kit for diagnostic in vitro detection of agents for use in the treatment of herpes virus infection, wherein the kit comprises:

[0042] a) a herpes virus polypeptide, said polypeptide comprising a sequence selected from the group consisting of (at least) the Cys-X10-His-X3-Cys-X4-Cys-X14-His-X6-Cys alphaherpesvirus subfamily zinc-finger motif, Cys-X12-His-X1-Cys-X4-Cys-X17-Cys betaherpesvirus subfamily zinc-finger motif and His-X3-Cys-X4-Cys gammaherpesvirus subfamily zinc finger motif of herpesvirus IE63 functional homologues;

[0043] b) a source of zinc, in order that when added to said polypeptide, a polypeptide/zinc complex is formed; and

[0044] C) means for enabling determination of any change in said polypeptide/zinc complex in the presence of an agent.

[0045] It may be appreciated that the polypeptide and zinc may be provided as a preformed polypeptide/zinc complex.

[0046] Determination of agents for use in the treatment of herpes virus infection is based on a change in the properties of said polypeptide/zinc complex when a test agent is added. Such a change may be determined by methods using 65Zn2+ or NMR, which can detect ejection of zinc from said polypeptide/zinc complex by a test agent as described earlier.

[0047] Typically, said polypeptide or polypeptide/zinc complex may be immobilised on a solid substrate which may be, for example, a well of a microtiter plate, cuvette, nitrocellulose or the like.

[0048] The present invention will now be further described by way of example only, with reference to the following methods and figures which show:

[0049]FIG. 1—comparison of protein sequences of herpesvirus IE63 and homologues. Alignment of amino acid sequences using the “Pileup” programme (Wisconsin Sequence Package, Version 9.0, Genetics computer Group) of IE63 and its homologues from various human and animal herpesviruses including alpha-, beta- and gammaherpesvirus subfamilies are shown.

[0050]FIG. 2—alignment of C-terminal region of IE63 and homoloques. Three alignments of the C-terminal region of IE63 and its homologues using the GCG “Pileup” programme are shown for alpha-, beta- and gammaherpesvirus subfamilies. The C-terminal region contains a conserved zinc finger motif within each subfamily of herpesvirus. Conserved residues are shown in bold and denoted by the single letter conserved amino acid residue underneath.

[0051]FIG. 3—Gel showing Purification of His tagged IE63 SDS PAGE gel showing the fractions containing IE63 obtained by purification on Qiagen Ni-NTA.

[0052]FIG. 4—Western Blot of IE63 Purification Western Blot of fraction obtained from purification of IE63 on Ni-NTA.

[0053]FIG. 5—Zinc election from IE63 monitored by spectrofluorimetry Zinc ejection assay performed on HSV-1 IE63 protein as described in (24). 25 μM TSQ and 0.5 μM IE63 added at time point X. 25 μM DIBA added at time point Y. Excitation wavelength 360 nm and emission wavelength 460 nm, sampling every 2 sec.

METHODS

[0054] Cytotoxicity. Both compounds azodicarbonamide (ADA, NSC 674447) and 2,2′,-dithiobisbenzamide (DIBA, NSC 654077) were dissolved at the appropriate concentration in 0.1% (v/v) dimethylsulphoxide (DMSO) in Eagle's modified medium. Confluent monolayers (2×106) of baby hamster kidney BHK21/C13 cells were incubated with various concentrations of either ADA or DIBA (1,10,100 μM) or as a control 0.1% (v/v) DMSO, and cell viability determined every day for 4 days by Trypan Blue exclusion staining (23).

[0055] Virus replication. Semi-confluent monolayers of BHK21/C13 cells (2×106) were pre-incubated with the appropriate drug concentration, 0.1% DMSO (v/v) or mock treated as a control for 24 h and subsequently infected at a multiplicity of infection (moi) of 5 plaque forming units (pfu)/cell with either herpes simplex virus type 1 (HSV-1) strain 17 or HSV-2 strain HG52 and harvested 24 h post-infection (pi). The virus yield was determined by releasing the virus into the supernatant by sonication and titration on BHK21/C13 cells. Results were expressed as pfu/106 cells and % reduction in yield as compared to the untreated control (23).

[0056] Plaque reduction assay. Confluent monolayers (4×106 cells) of BHK21/C13 cells were preincubated with the appropriate drug concentration, 0.1% DMSO(v/v) or mock treated as a control for 24 h and subsequently infected at a moi of 400 pfu/plate with either HSV-1 or HSV-2 and incubated for 48 h at 37° C. The cells were fixed and stained with Giemsa stain and the number of plaques counted. Tests of each drug concentration were performed in triplicate and the average of the 3 plates calculated. Results were expressed as pfu/plate and % of the number of plaques on the untreated control plates (23).

[0057] Expression and Purification of HSV 1 IE63.

[0058] Expression of N terminal His Tagged IE63

[0059]E. coli Novablue cells (Novagen) were transformed with a pET28 vector (Novagen) containing the IE63 gene. Cells were plated on L-Broth Agar containing Tetracycline (12.5 μg/ml) and Kanamycin (25 μg/ml) and incubated overnight at 37° C. The following day a single colony was inoculated into 10 ml of L-Broth containing tetracycline, chloramphenicol and 0.2% maltose and incubated at 3720 C. overnight. The next day this 10 ml culture was inoculated into 500 ml of L-Broth (containing tetracycline, chloramphenicol and maltose) and grown at 37° C. until the OD600 reached 1.0. MgSO4 was added to a final concentration of 10 mM and the λCE6 phage (Novagen) was added to a final concentration of 2×109 pfu/ml. The cells were grown for a further two hours and then harvested by centrifugation. The pellet of frozen cells was stored frozen at −20° C. until required. Protein expression was analysed by Western blot using the IE63 antibody.

[0060] Purification of His Tagged IE63

[0061] The pellet of frozen cells was thawed slowly on ice and resuspended in 5 ml of lysis buffer per 500 ml of culture.

[0062] Lysis Buffer

[0063] 2 mM Tris HCl pH 8

[0064] 100 mM NaCl

[0065] 0.5% NP-40

[0066] 20 mM imidazole

[0067] Protease inhibitor cocktail tablet (Boehringer). Cells were lysed by French pressing and the insoluble material pelleted by centrifugation at 4° C. and 15000 rpm. The supernatant is removed to a clean tube and 1 ml of Ni-NTA (Qiagen) resin is added per litre of starting culture. This mixture is then incubated with rotation at 4° C. for 2-3 hours. The Ni-NTA resin is pelleted by centrifugation at 3000 rpm for 1 min and the supernatant removed. The resin is then washed with 2 times 50 ml of lysis buffer (described above) followed by one wash with lysis buffer minus NP-40, one wash with lysis buffer plus 1M NaCl and finally one wash with original lysis buffer. The washed beads are then loaded into a 10 ml column (Biorad) and allowed to settle. The protein is eluted from the resin in four to five 1 ml aliquots of elution buffer

[0068] Elution buffer

[0069] 20 mM Tris HCl pH 8

[0070] 100 mM NaCl

[0071] 300 mM Imidazole

[0072] The fractions are then analysed by SDS PAGE and Western Blot for the presence of IE63.

[0073] Fractions containing IE63 are dialysed against 50 mM Tris pH 8 containing 10% glycerol before storing at −20° C.

EXAMPLE 1

[0074] Conservation of Zinc Finger Regions in Herpesvirus IE63 and Homologues.

[0075] Amino acid sequences of herpesvirus IE63 and its various human and animal counterparts were compared using the GCG “Pileup” alignment programme. It was observed that the spacing of the metal co-ordinating cysteine and histidine residues in the IE63 zinc finger (FIG. 1) are precisely conserved in all homologues within the alphaherpesvirus sub-family (Cys-X10-His-X3-Cys-X4-Cys-X14-His-X6-Cys) and for the other sub-families (FIG. 1) there is a similar conservation of spacing but the arrangements are different (betas; Cys-X12-His-X1-Cys-X4-Cys-X17-Cys gammas; His-X3-Cys-X4-Cys). The zinc finger lies at the extreme C-terminus of IE63 and its alphaherpesvirus and betaherpesvirus homologues, and towards the C-terminus in the gammaherpesvirus counterparts. Inspection of the database reveals that these three zinc finger arrangements are different from those present in other identified viral and cellular proteins.

EXAMPLE 2

[0076] Determination or cytotoxicity of ADA and DIBA. In view of the distinctive sequence conservation of the IE63 zinc finger two previously known zinc-ejecting anti-HIV-1 compounds, 2,2′-dithiobisbenzamide (DIBA) and azodicarbonamide (ADA) were tested for their effect on herpesvirus. To separate any effect on cell viability from a specific effect on virus replication, the effect of incubating BHK21/C13 cells in various concentrations of ADA, DIBA, and 0.1% (v/v) DMSO as a control, for up to 4 days was determined. Even at the highest concentration used (100 μM) 95% of the cells were viable compared to untreated BHK21/C13 cells (data not shown) Indeed any cytotoxicity observed was due to the DMSO in which the drugs were dissolved, as the cytotoxicity was equally great in those cells incubated with only DMSO (data not shown).

EXAMPLES 3

[0077] Antiviral effect of ADA and DIBA. Two experiments were carried out. In the first, the effect of varying concentrations of ADA and DIBA on the replication of HSV-1 was analysed. In the second, the effect on both HSV-1 and HSV-2 was determined. The results are summarised in Tables 1 and 2 respectively.

TABLE 1
VIRUS YIELD VIRUS YIELD % UNTREATED
(pfu/106 BHK cells) (pfu/BHK cell) CONTROL
HSV-1
0   8 × 108* 800  100%
0.1% DMSO 7.2 × 108 720   90%
 1 μM ADA 6.1 × 108 610   76%
 10 μM ADA 1.5 × 108 150   19%
100 μM ADA   9 × 106 9.0   11%
 1 μM DIBA 6.8 × 108 680   85%
 10 μM DIBA 1.6 × 108 160   20%
100 μM DIBA   2 × 107 20  2.5%

[0078]

TABLE 2
VIRUS YIELD VIRUS YIELD % UNTREATED
(pfu/106 BHK cells) (pfu/BHK cell) CONTROL
HSV-1
0 6.1 × 108* 610  100%
0.1% DMSO   6 × 108 600   98%
 1 μM ADA 9.3 × 107 93   15%
 10 μM ADA 8.5 × 106 8.5  1.4%
100 μM ADA 1.2 × 106 1.2 0.19%
 1 μM DIBA 1.2 × 108 120   20%
 10 μM DIBA 9.6 × 106 9.6  1.6%
100 μM DIBA 1.9 × 106 1.9 0.31%
HSV-2
0   7 × 107* 70  100%
0.1% DMSO 7.2 × 107 72  103%
 1 μM ADA 9.4 × 106 9.4   13%
 10 μM ADA 8.5 × 105 0.85  1.2%
100 μM ADA 2.3 × 105 0.23 0.33%
 1 μM DIBA 1.2 × 107 12   17%
 10 μM DIBA 1.4 × 106 1.4   2%
100 μM DIBA 3.1 × 105 0.31 0.44%

[0079] With both compounds there was a dose dependent reduction in virus yield. In experiment 1, DIBA appeared to have a greater antiviral effect, reducing the virus yield to 2.5% compared to 11% for ADA at 100 μM. However, in the second experiment, where the overall antiviral effect was greater, there was no significant difference between the effect of DIBA and ADA, with virus yield being reduced to less than 1% of the untreated control. Both HSV-1 and HSV-2 replication was equally affected.

EXAMPLE 4

[0080] Plaquing Efficiency in the Presence of ADA and DIBA. To determine if the reduction in virus yield seen in the previous experiment was due to a virucidal effect, inhibition of virus entry (adsorption penetration) or intracellular replication, a plaque reduction assay was carried out. Here, the ability of the virus to plaque was measured. An effect on the stability of the virus particle or virus entry would lead to a reduction in the number of plaques compared to the control untreated plates for a given amount of virus. In contrast, an effect on intracellular virus replication would not lead to a significant reduction in plaques. No significant reduction in HSV-1 or HSV-2 plaquing was seen with at most a 10% reduction (i.e. in the presence of the drug 90% of the number of plaques seen with untreated plates still remained) seen at the highest drug concentrations (data not shown). However, there was a reduction in the size of the plaques consistent with an effect on virus replication reducing the yield of progeny virus from each infected cell.

[0081] This experiment strongly suggests that the antiviral effect of DIBA seen in the previous experiment is due to an inhibition of intracellular replication.

EXAMPLE 5

[0082] Zinc Ejection Assay

[0083] Purified HSV-1 IE63 protein was prepared as described earlier for use in the zinc ejection assay. The zinc ejection assay for IE63 was carried out as described in (24) by substituting the IE63 protein for the p7NC protein. All chemicals were used at the same concentrations as described. Results, as measured by spectrofluorimetry are shown in FIG. 5.

[0084] It is understood that the above embodiments are merely representative of the present invention and should not be considered to be limiting thereof.

[0085] References

[0086] 1. Dannull J, et al (1994). EMBO J., 13, 1525-1533.

[0087] 2. Rice W G & Turpin J A (1996) Rev. Med. Virol., 6, 187-199.

[0088] 3. Domagala J M, et al (1997). Bioorganic & Medicinal Chem., 5, 569-579.

[0089] 4. Huang M, et al (1998) J Med. Chem., 41, 1371-1381.

[0090] 5. Davison A J & Clemaents J B. (1997). In; Topley and Wilson's Principles of Bacteriology, Virology and Imnunology (9th Edition), eds. B W J Mahy & L H Collier. Edward Arnold, London, pp309-323.

[0091] 6. Keating M R (1999). Mayo Clin. Proc., 74, 1266-1283

[0092] 7. Cassady K A & Whitley R J (1997). J. Antimicrob. Chemother., 39, 119-128.

[0093] 8. Emery V C (1998) Antivir. Ther., 3, 239-242.

[0094] 9. Field A K (1999). Antivir. Chem. chemother., 10, 219-232

[0095] 10. Phelan A & Clements J B. (1998). Samin. Virol., 8, 309-318.

[0096] 11. Panagiotidis C A, et al. (1997). J. Virol., 64, 3471-3485.

[0097] 12. Spengler M et al. (1998). Abstract, 23rd International Herpesvirus Workshop, York, UK.

[0098] 13. Sandri-Goldin R M (1998). Genes and Dev., 12, 868-878.

[0099] 14. Hardy W R & Sandri-Goldin R M. (1994). J. Virol., 68, 7790-7799.

[0100] 16. Choo Y & Klug A (1997). Curr. Opin. Struct. Biol., 7, 117-125.

[0101] 17. Mackay J P & Crossley M (1998). TIBS, 23, 1-4.

[0102] 18. Vaughan P J, et al (1992). Virology, 189, 377-384.

[0103] 19. Wadd S, et al. (1999). J. Biol. Chem., 274, 28991-28998.

[0104] 20. Zhi Y, et al (1999). Virology, 257, 341-351.

[0105] 21. Rice W G et al (1993). Nature, 361, 473-475.

[0106] 22. Rice W G et al (1995). Science, 270, 1194-1197.

[0107] 23. Dargan, D. J. (1998). In “Herpes Simplex Virus Protocols” Ed. S. M. Brown and A. R. MacLean, Humana Press.

[0108] 24. Rice et al (1996) Journal of. Medicinal. chemistry 39 3606-3616. (Evaluation of selected chemotypes in coupled cellular and molecular target based screens identifies novel HIV-1 zinc finger inhibitors).

[0109] 25. Frederickson, C. J. et al (1987). J. Neurosci.Meth., 20, 91-97.

1 18 1 512 PRT herpes simplex virus type 1 1 Met Ala Thr Asp Ile Asp Met Leu Ile Asp Leu Gly Leu Asp Leu Ser 1 5 10 15 Asp Ser Asp Leu Asp Glu Asp Pro Pro Glu Pro Ala Glu Ser Arg Arg 20 25 30 Asp Asp Leu Glu Ser Asp Ser Ser Gly Glu Cys Ser Ser Ser Asp Glu 35 40 45 Asp Met Glu Asp Pro His Gly Glu Asp Gly Pro Glu Pro Ile Leu Asp 50 55 60 Ala Ala Arg Pro Ala Val Arg Pro Ser Arg Pro Glu Asp Pro Gly Val 65 70 75 80 Pro Ser Thr Gln Thr Pro Arg Pro Thr Glu Arg Gln Gly Pro Asn Asp 85 90 95 Pro Gln Pro Ala Pro His Ser Val Trp Ser Arg Leu Gly Ala Arg Arg 100 105 110 Pro Ser Cys Ser Pro Glu Gln His Gly Gly Lys Val Ala Arg Leu Gln 115 120 125 Pro Pro Pro Thr Lys Ala Gln Pro Ala Arg Gly Gly Arg Arg Gly Arg 130 135 140 Arg Arg Gly Arg Gly Arg Gly Gly Pro Gly Ala Ala Asp Gly Leu Ser 145 150 155 160 Asp Pro Arg Arg Arg Ala Pro Arg Thr Asn Arg Asn Pro Gly Gly Pro 165 170 175 Arg Pro Gly Ala Gly Trp Thr Asp Gly Pro Gly Ala Pro His Gly Glu 180 185 190 Ala Trp Arg Gly Ser Glu Gln Pro Asp Pro Pro Gly Gly Gln Arg Thr 195 200 205 Arg Gly Val Arg Gln Ala Pro Pro Pro Leu Met Thr Leu Ala Ile Ala 210 215 220 Pro Pro Pro Ala Asp Pro Arg Ala Pro Ala Pro Glu Arg Lys Ala Pro 225 230 235 240 Ala Ala Asp Thr Ile Asp Ala Thr Thr Arg Leu Val Leu Arg Ser Ile 245 250 255 Ser Glu Arg Ala Ala Val Asp Arg Ile Ser Glu Ser Phe Gly Arg Ser 260 265 270 Ala Gln Val Met His Asp Pro Phe Gly Gly Gln Pro Phe Pro Ala Ala 275 280 285 Asn Ser Pro Trp Ala Pro Val Leu Ala Gly Gln Gly Gly Pro Phe Asp 290 295 300 Ala Glu Thr Arg Arg Val Ser Trp Glu Thr Leu Val Ala His Gly Pro 305 310 315 320 Ser Leu Tyr Arg Thr Phe Ala Gly Asn Pro Arg Ala Ala Ser Thr Ala 325 330 335 Lys Ala Met Arg Asp Cys Val Leu Arg Gln Glu Asn Phe Ile Glu Ala 340 345 350 Leu Ala Ser Ala Asp Glu Thr Leu Ala Trp Cys Lys Met Cys Ile His 355 360 365 His Asn Leu Pro Leu Arg Pro Gln Asp Pro Ile Ile Gly Thr Thr Ala 370 375 380 Ala Val Leu Asp Asn Leu Ala Thr Arg Leu Arg Pro Phe Leu Gln Cys 385 390 395 400 Tyr Leu Lys Ala Arg Gly Leu Cys Gly Leu Asp Glu Leu Cys Ser Arg 405 410 415 Arg Arg Leu Ala Asp Ile Lys Asp Ile Ala Ser Phe Val Phe Val Ile 420 425 430 Leu Ala Arg Leu Ala Asn Arg Val Glu Arg Gly Val Ala Glu Ile Asp 435 440 445 Tyr Ala Thr Leu Gly Val Gly Val Gly Glu Lys Met His Phe Tyr Leu 450 455 460 Pro Gly Ala Cys Met Ala Gly Leu Ile Glu Ile Leu Asp Thr His Arg 465 470 475 480 Gln Glu Cys Ser Ser Arg Val Cys Glu Leu Thr Ala Ser His Ile Val 485 490 495 Ala Pro Pro Tyr Val His Gly Lys Tyr Phe Tyr Cys Asn Ser Leu Phe 500 505 510 2 500 PRT herpes simplex virus type 2 2 Met Ala Thr Asp Ile Asp Met Leu Ile Asp Leu Gly Leu Asp Leu Ser 1 5 10 15 Asp Ser Glu Leu Glu Glu Asp Ala Leu Glu Arg Asp Glu Glu Gly Arg 20 25 30 Arg Asp Asp Pro Glu Ser Asp Ser Ser Gly Glu Cys Ser Ser Ser Asp 35 40 45 Glu Asp Met Glu Asp Pro Cys Gly Asp Gly Gly Ala Glu Ala Ile Asp 50 55 60 Ala Ala Ile Pro Lys Gly Pro Pro Ala Arg Pro Glu Asp Ala Gly Thr 65 70 75 80 Pro Glu Ala Ser Thr Pro Arg Pro Ala Ala Arg Arg Gly Ala Asp Asp 85 90 95 Pro Pro Pro Ala Thr Thr Gly Val Trp Ser Arg Leu Gly Thr Arg Arg 100 105 110 Ser Ala Ser Pro Arg Glu Pro His Gly Gly Lys Val Ala Arg Ile Gln 115 120 125 Pro Pro Ser Thr Lys Ala Pro His Pro Arg Gly Gly Arg Arg Gly Arg 130 135 140 Arg Arg Gly Arg Gly Arg Tyr Gly Pro Gly Gly Ala Asp Ser Thr Pro 145 150 155 160 Lys Pro Arg Arg Arg Val Ser Arg Asn Ala His Asn Gln Gly Gly Arg 165 170 175 His Pro Ala Ser Ala Arg Thr Asp Gly Pro Gly Ala Thr His Gly Glu 180 185 190 Ala Arg Arg Gly Gly Glu Gln Leu Asp Val Ser Gly Gly Pro Arg Pro 195 200 205 Arg Gly Thr Arg Gln Ala Pro Pro Pro Leu Met Ala Leu Ser Leu Thr 210 215 220 Pro Pro His Ala Asp Gly Arg Ala Pro Val Pro Glu Arg Lys Ala Pro 225 230 235 240 Ser Ala Asp Thr Ile Asp Pro Ala Val Arg Ala Val Leu Arg Ser Ile 245 250 255 Ser Glu Arg Ala Ala Val Glu Arg Ile Ser Glu Ser Phe Gly Arg Ser 260 265 270 Ala Leu Val Met Gln Asp Pro Phe Gly Gly Met Pro Phe Pro Ala Ala 275 280 285 Asn Ser Pro Trp Ala Pro Val Leu Ala Thr Gln Ala Gly Gly Phe Asp 290 295 300 Ala Glu Thr Arg Arg Val Ser Trp Glu Thr Leu Val Ala His Gly Pro 305 310 315 320 Ser Leu Tyr Arg Thr Phe Ala Ala Asn Pro Arg Ala Ala Ser Thr Ala 325 330 335 Lys Ala Met Arg Asp Cys Val Leu Arg Gln Glu Asn Leu Ile Glu Ala 340 345 350 Leu Ala Ser Ala Asp Glu Thr Leu Ala Trp Cys Lys Met Cys Ile His 355 360 365 His Asn Leu Pro Leu Arg Pro Gln Asp Pro Ile Ile Gly Thr Ala Ala 370 375 380 Ala Val Leu Glu Asn Leu Ala Thr Arg Leu Arg Pro Phe Leu Gln Cys 385 390 395 400 Tyr Leu Lys Ala Arg Gly Leu Cys Gly Leu Asp Asp Leu Cys Ser Arg 405 410 415 Arg Arg Leu Ser Asp Ile Lys Asp Ile Ala Ser Phe Val Leu Val Ile 420 425 430 Leu Ala Arg Leu Ala Asn Arg Val Glu Arg Gly Val Ser Glu Ile Asp 435 440 445 Tyr Thr Thr Val Gly Val Gly Ala Gly Glu Thr Met His Phe Tyr Ile 450 455 460 Pro Gly Ala Cys Met Ala Gly Leu Ile Glu Ile Leu Asp Thr His Arg 465 470 475 480 Gln Glu Cys Ser Ser Arg Val Cys Glu Leu Thr Ala Ser His Thr Ile 485 490 495 Ala Pro Leu Tyr 500 3 470 PRT Equine herpesvirus 1 3 Met Ala Leu Ser Ser Val Ser Ser Cys Glu Pro Met Glu Asp Glu Met 1 5 10 15 Ser Ile Met Gly Ser Asp Thr Glu Asp Asn Phe Thr Gly Gly Asp Thr 20 25 30 Cys Ala Glu Ala Thr Arg Gly Leu Val Asn Lys Ser Ala Phe Val Pro 35 40 45 Thr Gln Thr Val Gly Thr Val Ser Ala Leu Arg Asn Val Val Gly Asp 50 55 60 Pro Pro Lys Ser Val Val Val Ser Phe Ser Ala Ser Pro Gln Arg Ala 65 70 75 80 Gln Pro Ser Asn Pro Lys Ser Glu Arg Pro Ala Phe Gly His Gly Arg 85 90 95 Arg Asn Arg Arg Arg Pro Phe Arg Arg Asn Asn Trp Lys Gln Gln Gln 100 105 110 Arg Gly Trp Glu Lys Pro Glu Pro Glu Asn Val Pro Ala Arg Gln Ser 115 120 125 Ala Gly Ser Trp Pro Lys Arg Ser Ser Leu Pro Val His Met Arg Leu 130 135 140 Gly Gln Arg Gly Gly Asp Ser Ser Ser Ala Asp Ser Gly His Gly Gly 145 150 155 160 Ala Gly Pro Ser Asp Arg Trp Arg Phe Lys Thr Arg Thr Gln Ser Val 165 170 175 Ala Arg Val His Arg Asn Arg Arg Arg Gly Asn Ala Asn His Gly Ser 180 185 190 Asn Thr Pro Gly Arg Ser Ala Gly Asp Arg Leu Asn Ala Ala Ala Ala 195 200 205 Ser Ser Ile Ala Asp Val Cys Arg Arg Val Thr Ser Ser Arg Ile Gly 210 215 220 Glu Met Phe His Gly Ala Arg Glu Thr Leu Thr Thr Pro Val Lys Asn 225 230 235 240 Gly Gly Phe Arg Ala Glu Asn Ser Ser Pro Trp Ala Pro Val Leu Gly 245 250 255 Phe Gly Ser Asp Gln Phe Asn Pro Glu Ala Arg Arg Ile Thr Trp Asp 260 265 270 Thr Leu Val Glu His Gly Val Asn Leu Tyr Lys Leu Phe Glu Val Arg 275 280 285 Ser His Ala Ala Glu Ala Ala Arg Ser Leu Arg Asp Ala Val Met Arg 290 295 300 Gly Glu Asn Leu Leu Glu Ala Leu Ala Ser Ala Asp Glu Thr Leu Ser 305 310 315 320 Trp Cys Lys Met Ile Val Thr Lys Asn Leu Pro Met Arg Thr Arg Asp 325 330 335 Pro Ile Ile Ser Ser Ser Val Ala Leu Leu Asp Asn Leu Arg Leu Lys 340 345 350 Leu Glu Pro Phe Met Arg Cys Tyr Leu Ser Ser Ser Gly Ser Pro Thr 355 360 365 Leu Ala Glu Leu Cys Asp His Gln Arg Leu Ser Asp Val Ala Cys Val 370 375 380 Pro Thr Phe Met Phe Val Met Leu Ala Arg Ile Ala Arg Ala Val Gly 385 390 395 400 Ser Gly Ala Glu Thr Val Ser Arg Asp Ala Leu Gly Pro Asp Gly Arg 405 410 415 Val Leu Ala Asp Tyr Val Pro Gly Ala Cys Leu Ala Gly Thr Leu Glu 420 425 430 Ala Ile Asp Ala His Lys Arg Arg Cys Lys Ala Asp Thr Cys Ser Leu 435 440 445 Val Ser Ala Tyr Thr Leu Val Pro Val Tyr Leu His Gly Lys Tyr Phe 450 455 460 Tyr Cys Asn Gln Ile Phe 465 470 4 467 PRT Equine herpesvirus 4 4 Met Ala Leu Ser Ser Val Ser Ser Cys Glu Pro Met Asp Asp Glu Met 1 5 10 15 Ser Ile Met Gly Ser Asp Thr Asp Asp Thr Leu Gly Gly Ser Cys Val 20 25 30 Glu Ala Ala Gln Ser Ala Val Val Asn Lys Arg Ala Phe Glu Met Ser 35 40 45 Glu Ser Thr Gly Thr Met Ser Thr Ile Arg Asn Val Val Ser Glu Val 50 55 60 Pro Lys Ser Leu Val Val Ser Phe Ala Ala Ser Pro Lys Asn Pro Lys 65 70 75 80 Pro Gln Asn Thr Thr Ser Glu Arg Ser Ala Phe Pro His Gly Arg Lys 85 90 95 Asn Arg Arg Arg Pro Phe Arg Arg Asn Asn Trp Lys Gln Arg Ala Trp 100 105 110 Glu Lys Gln Ser Gln Glu Ala Ala Pro Ala Asn Gln Gly Ser Arg Asn 115 120 125 Trp Pro Lys Arg Ser Ser Met Pro Val His Met Arg Leu Gly His Arg 130 135 140 Ser Gly Asp Phe Gln Ser Ala Asp Ala Gly His Cys Thr Ala Gly Pro 145 150 155 160 Ser Gly Gly Trp Arg Phe Lys Thr Arg Thr His Ser Ala Ser Arg Val 165 170 175 Tyr His Asn Arg Gln Arg Gly Asn Thr Asn Lys Ser Gly Asn Ala Ser 180 185 190 Ser Arg Ser Ser Gly Asp Arg Leu Asn Ala Ala Ala Ala Asn Ala Ile 195 200 205 Ala Asp Val Ser Lys Arg Val Thr Ser Ser Arg Ile Ser Asp Met Phe 210 215 220 His Gly Ala Arg Glu Thr Leu Thr Ser Pro Val Lys Asn Gly Gly Phe 225 230 235 240 Arg Ala Glu His Ser Ser Pro Trp Ser Pro Val Leu Asn Phe Gly Leu 245 250 255 Glu Gln Phe Asn Pro Glu Gly Arg Arg Ile Thr Trp Asp Thr Leu Val 260 265 270 Thr His Gly Glu Asn Leu Tyr Lys Leu Phe Glu Val Arg Ser His Ala 275 280 285 Ala Glu Ala Ala Arg Ser Leu Arg Asp Leu Val Met Arg Gly Glu Asn 290 295 300 Leu Leu Glu Ala Leu Ala Ser Ala Asp Glu Thr Ile Ser Trp Cys Lys 305 310 315 320 Met Ile Ile Thr Lys Asn Leu Pro Met Arg Thr Arg Asp Pro Ile Ile 325 330 335 His Ser Ser Ile Ala Leu Leu Glu Asn Leu Arg Leu Lys Leu Glu Pro 340 345 350 Phe Met Arg Cys Tyr Leu Ser Ser Ser Gly Ser Pro Thr Leu Ala Glu 355 360 365 Leu Cys Asp His Gln Arg Leu Ser Asp Val Ala Cys Val Pro Thr Phe 370 375 380 Met Phe Val Thr Leu Ala Arg Ile Ala Arg Ala Val Gly Ser Gly Ala 385 390 395 400 Glu Ala Val Ser Pro Asp Ala Leu Gly Pro Ala Gly His Ala Leu Ala 405 410 415 Asn Tyr Val Pro Gly Thr Cys Leu Ala Gly Thr Leu Glu Ala Ile Asp 420 425 430 Leu His Lys Arg Arg Cys Lys Glu Ser Thr Cys Ser Leu Val Ser Ser 435 440 445 Tyr Thr Leu Val Pro Val Tyr Leu His Gly Lys Tyr Phe Tyr Cys Asn 450 455 460 Gln Ile Phe 465 5 400 PRT Bovine herpesvirus 1 5 Met Ala Asp Pro Glu Ile Ala Thr Leu Ser Thr Ala Ser Glu Ser Asp 1 5 10 15 Asp Leu Ser Leu Phe Gly Ser Asp Arg Glu Glu Asp Asp Glu Ala Pro 20 25 30 Ser Leu Ala Pro Ala Leu Arg Ser Val Val Gly Gln Val Arg Lys Arg 35 40 45 Lys Leu Glu Gly Ala Glu Asp Glu Pro Met Pro Ala Glu Pro Pro Gly 50 55 60 Glu Gly Ala Ala Ser Gly Asp Gly Gly Pro Ala Glu Ala Pro Pro Ala 65 70 75 80 Arg Arg Ala Arg Val Arg Pro Arg Arg Pro Arg Arg Arg Pro Arg Arg 85 90 95 Arg Gln Pro Ala Gly Glu Gln Arg Ser Arg Gly Pro Ala Ala Lys Arg 100 105 110 Glu Ala Ala Leu Ala Thr Ser Ser His Gly Gly Gly Gly Ala Ala Ala 115 120 125 Arg Ser Ile Gly Ser Ser Leu Arg Leu Ala Arg Ser Leu Ala Glu Ala 130 135 140 Ala Gln Arg Ala Thr Ala Glu Arg Val Thr Ala Val Phe Ala Gly Ala 145 150 155 160 Arg Leu Asp Leu Met Arg Pro Val Gln Asn Gly Gly Phe Arg Ala Ala 165 170 175 Gly Val Ser Pro Trp Ala Ala Val Leu Asp Phe Gly Ala Glu Gln Phe 180 185 190 Val Pro Glu Gly Arg Arg Val Thr Trp Glu Thr Leu Met Phe His Gly 195 200 205 Arg Asp Leu Tyr Arg Met Phe Glu Val Arg Pro His Ala Ala Gln Ala 210 215 220 Ala Arg Ala Leu Arg Asp Leu Val Leu Arg Ser Ala Asn Leu Val Asp 225 230 235 240 Ala Leu Ala Ser Ala Asp Glu Cys Leu Thr Trp Cys Lys Phe Ile Ala 245 250 255 Thr Lys Asn Leu Arg Leu Arg Thr Lys Asp Pro Ile Val Ala Thr Ala 260 265 270 Gly Ala Val Leu Glu Asn Leu Arg Leu Lys Leu Ala Pro Phe Leu Arg 275 280 285 Cys Tyr Leu Arg Gly Arg Gly Leu Pro Ser Leu Glu Glu Leu Cys Ala 290 295 300 Ala Arg Arg Leu Ser Leu Ala Thr Cys Pro Ala Ser Tyr Met Phe Val 305 310 315 320 Met Leu Ala Arg Leu Ser Arg Ala Val Arg Ser Gly Ala Glu Cys Val 325 330 335 Pro Leu Leu Glu Val Thr Val Gly Asp Ala Pro Phe Glu Glu Tyr Ile 340 345 350 Pro Gly Thr Cys Val Ala Gly Leu Ile Asp Ala Leu Asp Thr His Lys 355 360 365 Gln Ala Cys Asp Ser Met Thr Cys Lys Leu Val Ala Asn Phe Thr Leu 370 375 380 Val Pro Val Tyr Met His Gly Lys Tyr Phe Tyr Cys Asn Glu Ile Phe 385 390 395 400 6 361 PRT Pseudorabies virus 6 Met Glu Asp Ser Gly Asn Ser Ser Gly Ser Glu Ala Ser Arg Ser Gly 1 5 10 15 Ser Glu Glu Arg Arg Pro Val Arg Glu Arg Leu Gly Ser Arg Pro Pro 20 25 30 Glu Arg Arg Pro Val Arg Ala Arg Leu Gly Ala Ile Arg Arg Arg Arg 35 40 45 Gly Gly Arg Gly Gly Arg Ala Ala Arg Gln Ala Leu Arg Gln Arg Arg 50 55 60 Arg Gln Gln Gln Gln Gln Gln Arg Gln Gln Gln His Gln Arg Arg Arg 65 70 75 80 Gln Glu Ala Asp Arg Pro Asp Gly Gly Pro Asp Ala Pro Pro Asp Arg 85 90 95 Leu Ser Glu Ser Ala Arg Ala Ala Val Ser Ala Thr His Ala Arg Val 100 105 110 Gly Ala Thr Arg Val Asn Glu Leu Phe Ala Ser Ala Arg His Asp Leu 115 120 125 Ser Arg Pro Val Phe Asn Asp Gly Phe Arg Ala Ala Gly Ser Ser Pro 130 135 140 Trp Ala Ala Val Leu Glu Phe Gly Ala Glu Gln Phe Thr Pro Asp Gly 145 150 155 160 Arg Arg Val Thr Trp Glu Thr Leu Met Phe His Gly Ala Asp Leu His 165 170 175 Arg Leu Phe Glu Val Arg Pro His Ala Thr Glu Ala Ala Arg Val Leu 180 185 190 Arg Glu Met Val Leu Leu Asn Glu Gly Leu Thr Glu Ser Leu Ala Ser 195 200 205 Ala Asp Glu Thr Leu Thr Trp Val Lys Leu Ile Leu Thr Lys Gly Leu 210 215 220 Thr Leu Arg Thr Leu Asp Pro Ile Val Ala Thr Ala Gly Ala Val Leu 225 230 235 240 Gln Asn Leu Arg Leu Lys Leu Gly Pro Phe Leu Arg Cys Tyr Leu Arg 245 250 255 Asp Thr Pro Val Asp Glu Leu Val Arg Arg Arg Arg Leu Arg Asp Val 260 265 270 Arg Cys Ile Val Thr Tyr Thr Leu Val Met Leu Ala Arg Ile Ala Arg 275 280 285 Val Val Glu Arg Gly Ser Ser Cys Val Leu Pro Glu Asp Leu Gly Asp 290 295 300 Ser Pro Val Pro Leu Glu Glu Tyr Val Pro Gly Ala Cys Leu Gly Gly 305 310 315 320 Ile Met Asp Ala Leu Asp Ser His Lys Thr Gly Cys Asp Ala Pro Thr 325 330 335 Cys Arg Leu Thr Cys Ser Tyr Thr Leu Val Pro Val Tyr Met His Gly 340 345 350 Lys Tyr Phe Tyr Cys Asn His Leu Phe 355 360 7 452 PRT Varicella-zoster virus 7 Met Ala Ser Ala Ser Ile Pro Thr Asp Pro Asp Val Ser Thr Ile Cys 1 5 10 15 Glu Asp Phe Met Asn Leu Leu Pro Asp Glu Pro Ser Asp Asp Phe Ala 20 25 30 Leu Glu Val Thr Asp Trp Ala Asn Asp Glu Ala Ile Gly Ser Thr Pro 35 40 45 Gly Glu Asp Ser Thr Thr Ser Arg Thr Val Tyr Val Glu Arg Thr Ala 50 55 60 Asp Thr Ala Tyr Asn Pro Arg Tyr Ser Lys Arg Arg His Gly Arg Arg 65 70 75 80 Glu Ser Tyr His His Asn Arg Pro Lys Thr Leu Val Val Val Leu Pro 85 90 95 Asp Ser Asn His His Gly Gly Arg Asp Val Glu Thr Gly Tyr Ala Arg 100 105 110 Ile Glu Arg Gly His Arg Arg Ser Ser Arg Ser Tyr Asn Thr Gln Ser 115 120 125 Ser Arg Lys His Arg Asp Arg Ser Leu Ser Asn Arg Arg Arg Arg Pro 130 135 140 Thr Thr Pro Pro Ala Met Thr Thr Gly Glu Arg Asn Asp Gln Thr His 145 150 155 160 Asp Glu Ser Tyr Arg Leu Arg Phe Ser Lys Arg Asp Ala Arg Arg Glu 165 170 175 Arg Ile Arg Lys Glu Tyr Asp Ile Pro Val Asp Arg Ile Thr Gly Arg 180 185 190 Ala Ile Glu Val Val Ser Thr Ala Gly Ala Ser Val Thr Ile Asp Ser 195 200 205 Val Arg His Leu Asp Glu Thr Ile Glu Lys Leu Val Val Arg Tyr Ala 210 215 220 Thr Ile Gln Glu Gly Asp Ser Trp Ala Ser Gly Gly Cys Phe Pro Gly 225 230 235 240 Ile Lys Gln Asn Thr Ser Trp Pro Glu Leu Met Leu Tyr Gly His Glu 245 250 255 Leu Tyr Arg Thr Phe Glu Ser Tyr Lys Met Asp Ser Arg Ile Ala Arg 260 265 270 Ala Leu Arg Glu Arg Val Ile Arg Gly Glu Ser Leu Ile Glu Ala Leu 275 280 285 Glu Ser Ala Asp Glu Leu Leu Thr Trp Ile Lys Met Leu Ala Ala Lys 290 295 300 Asn Leu Pro Ile Tyr Thr Asn Asn Pro Ile Val Ala Thr Ser Lys Ser 305 310 315 320 Leu Leu Glu Asn Leu Lys Leu Lys Leu Gly Pro Phe Val Arg Cys Leu 325 330 335 Leu Leu Asn Arg Asp Asn Asp Leu Gly Ser Arg Thr Leu Pro Glu Leu 340 345 350 Leu Arg Gln Gln Arg Phe Ser Asp Ile Thr Cys Ile Thr Thr Tyr Met 355 360 365 Phe Val Met Ile Ala Arg Ile Ala Asn Ile Val Val Arg Gly Ser Lys 370 375 380 Phe Val Glu Tyr Asp Asp Ile Ser Cys Asn Val Gln Val Leu Gln Glu 385 390 395 400 Tyr Thr Pro Gly Ser Cys Leu Ala Gly Val Leu Glu Ala Leu Ile Thr 405 410 415 His Gln Arg Glu Cys Gly Arg Val Glu Cys Thr Leu Ser Thr Trp Ala 420 425 430 Gly His Leu Ser Asp Ala Arg Pro Tyr Gly Lys Tyr Phe Lys Cys Ser 435 440 445 Thr Phe Asn Cys 450 8 473 PRT Marek′s disease virus 8 Met Ser Val Asp Ala Phe Ser Arg Glu Ser Asp Asp Met Met Ser Leu 1 5 10 15 Leu Asp Tyr Asp Phe Ile Glu Gly Ser Ser Ser Asp Glu Asn Ala Glu 20 25 30 Val Thr Glu Met Glu Thr Ser Ala Lys Thr Ala Asn Asn Lys Asn Glu 35 40 45 Val Leu Phe Ala Pro Pro Cys Thr Gln Glu Leu Leu Thr Glu Arg Pro 50 55 60 Ser Pro Asp Ser Lys Asn Ser Gln Gly Asp Asp Asp Ser Asn Ser Ile 65 70 75 80 Tyr Gly Asn Val Ile Arg Asp Ala Gln His Ser Ala Ser Arg Tyr Ala 85 90 95 Thr Arg Cys Leu Asp Asn Ala Ile Pro Arg Lys Arg Leu Arg Leu Ala 100 105 110 Asn Leu Thr Val Asp Ser Ala Cys Ile Ser Gln Thr Lys Arg Pro His 115 120 125 Gly Thr Gly Asn Arg Lys Gln Tyr His Arg Arg Asn Phe Pro Met Ser 130 135 140 Pro Thr Ser Gln Glu Lys Ile His Leu Arg Leu His Asn Arg Leu Gly 145 150 155 160 Ser Arg Ser Glu Lys Gln Gln Arg Ser Leu Asn Tyr Asp Arg Arg Leu 165 170 175 Gln Glu Gly His His Arg Arg Arg Phe Tyr Ser Glu Arg Arg Ile Tyr 180 185 190 Asp Gln Asn His Ser His His Arg Thr His Asp Ile Arg Val Pro Leu 195 200 205 Glu Lys Tyr Arg Val Ser Arg Gln His Asp Leu Pro Val His Glu Glu 210 215 220 Leu Asn Glu Ile Leu Gln Arg Glu Lys His Arg Leu Ala Ser Ile Ser 225 230 235 240 Asn Glu Cys Asp Phe Arg Val Ser Ser Lys Asn Arg Trp Ala Ala Val 245 250 255 Leu Thr Phe Ser Ser Asn Ala Glu Ser Thr Leu Cys Gly Pro Gln Ile 260 265 270 Thr Trp Glu Tyr Leu Leu His Ala Gly Pro Glu Leu Arg Asn Thr Phe 275 280 285 Glu Ile Arg Pro Arg Ile Ser Leu Gln Ala Ser Ala Ala Arg Glu Ala 290 295 300 Val Leu Arg Gly Glu Ser Phe Ile Ala Ala Leu Gly Ser Ala Glu Glu 305 310 315 320 Thr Leu Ser Trp Leu Lys Leu His Ala Val Leu Lys Leu Arg Leu Val 325 330 335 Asn His Asp Pro Ile Phe Lys Thr Ala Gly Ala Val Leu Asp Asn Leu 340 345 350 Arg Leu Lys Leu Ala Pro Ile Met Met Cys Lys Tyr Gly Thr Glu Lys 355 360 365 Arg Ser Met Gly Asp Met Leu Arg Arg Ser Ala Pro Glu Asp Ile Asn 370 375 380 Asp Ser Leu Thr Leu Cys Leu Ile Leu Leu Ser Arg Ile Arg Arg Val 385 390 395 400 Met His Arg Thr Ser Gly Ser Lys Tyr Ser Tyr Met Ile Asp Pro Arg 405 410 415 Gly Cys Met Ile Asp Tyr Val Pro Gly Glu Cys Met Thr Asn Ile Leu 420 425 430 Arg Tyr Val Asp Ala His Thr Arg Arg Cys Ser Asp Pro Ala Cys Asn 435 440 445 Leu Tyr Ile Ser Cys Thr Leu Met Pro Ile Tyr Ile His Gly Arg Tyr 450 455 460 Phe Tyr Cys Asn Thr Leu Phe Gly Met 465 470 9 515 PRT Human herpesvirus 6 9 Met Tyr Pro Arg Gly Val Lys Arg Ser His His Asp Tyr His Arg Gln 1 5 10 15 Thr Ala Phe Arg Thr Ile Lys Arg Ser Thr His Arg Gln Thr Ser Lys 20 25 30 Phe Ile Ser His Phe Ala Lys Asn Phe Arg Gly Lys Leu Ala Pro Leu 35 40 45 Lys Gln Leu Asp Glu Ser Arg Leu Asp Ala Leu Ser Leu Thr Glu Leu 50 55 60 Glu Gln Leu Lys Thr Ile Ile Glu Glu Lys Gln Gln Glu Lys Arg Ala 65 70 75 80 Gln Asn Asn Ala Ile Thr Phe Leu Pro Asn Leu Pro Thr Val Pro Phe 85 90 95 Ala Asp Thr Asn Phe Ser Leu Lys Ser Leu Gly Leu Arg Pro Tyr Asn 100 105 110 Gly Asp Ala Arg Asp Pro Lys Gln Arg Ile Arg Asp Arg Phe Pro Gln 115 120 125 Thr His Glu Arg Ile Cys Leu Leu Thr Asn Asp Ile Leu Glu Thr Asp 130 135 140 Leu Leu Leu Arg Tyr Arg Gln Cys Leu Asp Ser Leu Thr Arg Glu Glu 145 150 155 160 Asn Gln Gln Leu Met Gly Asp Arg Ile Phe Ser Leu Thr Asn Ser Pro 165 170 175 Cys Leu Ala Phe Thr Val Ala Thr Val Glu Glu Ala Cys Ser Tyr Phe 180 185 190 Lys Phe His Asp Leu His Asn Leu Pro Val Asn Pro Gln Asp Leu Phe 195 200 205 Met Tyr Thr Ile Thr Val Met Lys Phe Glu Phe Phe Asn Lys Leu Asn 210 215 220 Met Ala Lys Leu Thr Cys Val Phe Asn Asp Asn Gly His Gly Asp Ile 225 230 235 240 Glu Tyr Arg Lys Leu Arg Gln Leu Cys Gly Lys Pro Val Leu Asp Arg 245 250 255 Glu Met Pro Asn Ser Glu Leu Glu Val Gln Gln Gln Thr Pro Asp Ser 260 265 270 Phe Arg His Pro Ile Gln Gln Ala Met Ser Ile Val Val Thr Phe Ala 275 280 285 Arg Ile Leu Arg Gln Ile Lys Glu Gln Ile Ile Gln Thr Lys Lys Pro 290 295 300 Gln Phe Ile Arg Asp Phe Asp Thr Gly Arg Val Ala Glu Arg Tyr Glu 305 310 315 320 Cys Gly Leu Met Ser Arg Leu Ile Gly Lys Gln Phe Ser Asn His Lys 325 330 335 Cys Asp Asp Val Ser Cys Gln Asn Arg Ile Glu Arg Ile Met Ala Pro 340 345 350 Trp Lys Pro Ser Leu Phe Phe Cys Thr Tyr Phe Ala Lys Asp Ala Pro 355 360 365 Lys Phe Lys Leu Phe Pro Asn Phe Pro Glu Glu Tyr Arg Asn Leu Ser 370 375 380 Phe Thr Cys Pro Lys Val Asp Thr Glu Pro Ser Cys Ser Tyr Ser Thr 385 390 395 400 Asn His Asp Leu Pro Gln Thr Ser His Arg Ser His Lys Asn His Gly 405 410 415 Thr Pro Lys Val Lys Ser Lys Val Cys Val Glu Lys Pro Asp Thr Ser 420 425 430 Ile Leu Thr Thr Thr Lys Thr Thr Thr Glu Ile Leu Ile Glu Glu Ser 435 440 445 Met Glu Thr Asp Asn Lys Ile Pro Asn Pro Arg Glu Leu Asn Phe Asn 450 455 460 Gln Ala Lys Gln Glu Glu Ile Val Ile Ile Asn Ile Asn Glu Asn Val 465 470 475 480 Asn Ser Lys His Glu Ser Glu Ser Ser Val Glu Met Asp Leu Asp Leu 485 490 495 Asp Tyr Glu Ala Asp Thr Cys Glu Thr Asn Leu Asn Ala Cys Ser Ser 500 505 510 Asp Ser Glu 515 10 516 PRT Human herpesvirus 7 10 Met Tyr Pro Arg Gly Val Lys Lys Asn Val Leu Gly Arg Gln Arg Tyr 1 5 10 15 Gly Leu Lys Thr Ile Lys Arg Thr Leu Val His Lys Pro Ala Asn Lys 20 25 30 Tyr Val Ser Arg Phe Thr Lys Gln Phe His Arg Arg Ile Ile Pro Ile 35 40 45 Lys Gln Leu Asp Glu Ser Lys Leu Asp Ala Leu Ser Leu Arg Glu Leu 50 55 60 Glu Gln Leu Lys Leu Ile Ile Glu Glu Lys Gln Glu Glu Lys Arg Ala 65 70 75 80 Gln Thr His Ala Leu Thr Phe Phe Ala Asn Leu Pro Thr Ala Pro Phe 85 90 95 Gly Ser Ser Tyr Thr Ala Glu Ala Leu Gly Leu Arg Lys Tyr Ser Gly 100 105 110 Glu Ala Arg Asp Pro Ala His Arg Ile Arg Asp Arg Phe Pro Arg Asn 115 120 125 His Glu Lys Ile Tyr Leu Glu Lys Glu Glu Leu Met Thr Thr Asp Leu 130 135 140 Leu Leu Arg Tyr Lys Asn Cys Leu Asn Ser Leu Asn Arg Glu Gln His 145 150 155 160 Gln Gln Ile Leu Gly Asp Arg Val Phe Ser Leu Thr Asn Ser Pro Ser 165 170 175 Leu Ala Phe Ser Leu Ala Ile Ile Glu Glu Ala Cys Ile Tyr Tyr Lys 180 185 190 Tyr His Phe Val His Asn Leu Pro Ile Asp Pro Gln Asp Leu Phe Met 195 200 205 Tyr Thr Ile Thr Ile Met Lys Phe Glu Tyr Phe Asn Lys Leu Asn Met 210 215 220 Ala Lys Leu Cys Cys Val Phe Asn Asp Asn Gly His Gly Asp Ile Glu 225 230 235 240 Tyr Arg Ile Phe Arg Gln Leu Cys Gly Lys Pro Val Tyr Asp Arg Asp 245 250 255 Met Pro Asn Thr Glu Tyr Glu Val Gln Gln Gln Thr Pro Gly Ser Phe 260 265 270 Gln Tyr Pro Ala Gln Gln Ala Leu Ser Phe Ile Val Thr Phe Ala Arg 275 280 285 Ile Leu Arg Gln Ile Lys Glu Arg Ile Leu Gln Thr Lys Gln Pro Gln 290 295 300 Phe Ile Arg Asp Phe Asp Gln Asp Arg Val Ser Glu Gln Tyr Gln Cys 305 310 315 320 Gly Met Ile Ser Arg Leu Val Gly Asp Gln Phe Asn Asn His Gln Cys 325 330 335 Asp Asp Ile Gly Cys Gln Thr Arg Ile Gln Arg Met Met Ser Pro Trp 340 345 350 Lys Pro Ser Leu Tyr Phe Cys Thr Tyr Leu Pro Lys Glu Phe Val Glu 355 360 365 Phe Gly Leu His Pro Asn Met Pro Glu Glu Tyr Asn Ser Phe Asn Val 370 375 380 Ala Cys Ser Thr Thr Pro Ser Cys Ser Phe Ala Ser Gln Gln Ser Lys 385 390 395 400 Gln Thr Val Gln Leu Asn Leu Gln Thr Lys Lys Gln Ala Lys Cys Lys 405 410 415 Lys Leu Leu Thr Ala Asp Lys Thr Asn Lys Gly Gln Lys Thr Asn Glu 420 425 430 Leu Arg Glu Asn Arg Leu Lys Lys Asp Trp Ser Lys Glu Val Asp Ser 435 440 445 Ile Asp Phe Glu Thr Asn Thr Thr Leu Gln Glu Asp Glu Thr Arg Phe 450 455 460 Val Phe Ile Glu Asn Asp Thr Ser Met Lys Ser Ala Lys Ile Lys Glu 465 470 475 480 Asn Asn Gly Glu Glu Asn Ser Asp Asn Glu Met Glu Leu Asp Leu Asp 485 490 495 Tyr Glu Asp Val Glu Thr Cys Glu Thr Asp Ile Asn Asp Thr Asp Ser 500 505 510 Asp Asp Ser Asp 515 11 841 PRT Murine cytomegalovirus 11 Met Leu Arg Thr Gly Val Lys Arg Arg Leu Gly Pro Phe Ala Gly Tyr 1 5 10 15 Asp Glu Asp Asp Ala Ala Thr Gly Gly Val Ser Arg Arg Ser Lys Tyr 20 25 30 Ser Gln Gln Gln Ser Gln His Tyr Tyr Tyr Gly His Asn Gln Ser Ser 35 40 45 Tyr Arg Asp Ser Gly Ala Ser His Pro Asn Trp Lys Arg Asn Ala His 50 55 60 Leu Met Pro Pro Pro Leu Ser Ser Pro Ser Ser Pro Pro Pro Gln Tyr 65 70 75 80 Asp Lys Asn Ile Ala Ala Leu Thr His Leu Asn Lys Lys Leu Asp Cys 85 90 95 Leu Gly Pro Asp Asp Leu Glu Cys Leu Lys Ala Met Ile Arg Ile Arg 100 105 110 Glu Ala Arg Ala Gln Gly Arg Arg Pro Glu Pro Ser Ser Ala Pro Ser 115 120 125 Ile Leu Glu Ser Ser Leu Val Ser Ser Asn Asn Ser Asn Asn Asn Thr 130 135 140 Thr Leu Ser Leu Gly Gly Gly Gly Gly Gly Asp Tyr His Arg Gln Thr 145 150 155 160 Ser Pro Asp Ile Arg Asp Tyr Thr Thr Gly Ser Leu Gly Leu Cys Met 165 170 175 Phe Pro Met Asp Leu Pro Asp Pro Ile Lys Leu Leu Glu Asn Arg Tyr 180 185 190 Thr Asp Asn Asp Arg His Ala Pro Ala Val Val Thr His Asp Glu Leu 195 200 205 Ile Asn Thr Asn Tyr Leu Leu Leu Phe Arg Lys His Phe Asp Ala Leu 210 215 220 Pro Pro Glu Glu Leu Arg Val Leu Val Gln Asp Arg Thr Phe Ala Ile 225 230 235 240 Asn Asn Ala Pro Ser Leu Asp Val Val Ala Ala Met Ala Asp Glu Asn 245 250 255 Leu Thr Tyr Val Lys Phe His Arg Val His Asn Leu Pro Val Asn Pro 260 265 270 Lys Asp Leu Tyr Met Ser Thr Leu Gly Leu Ile Lys Tyr Ala Thr Phe 275 280 285 Asn Lys Leu Asn Leu Gly Glu Leu Ser Cys Leu Leu Asp Ser Pro Gly 290 295 300 Gly Gly Gly Ser Asp Arg Glu Tyr His Ile Leu Arg Gln Ile Ala Asn 305 310 315 320 Lys Pro Ala Ser Pro Cys Arg Lys Gly Gly Ser Ser Ala Ala Ala Ala 325 330 335 Ala Ser Phe Asp Val Leu Arg Arg Pro Pro Leu Ser Phe Lys His Pro 340 345 350 Leu Gln Gln Ala Leu Ala Leu Ile Ala Ser Phe Ala Arg Ile Val Gly 355 360 365 Val Ile Arg Arg Arg Ser Leu Arg His Ser Gly Pro Phe Phe Ile Arg 370 375 380 Asp Phe Asp Asp Thr Gly Ala Thr Asp Ser Tyr Arg Cys Gly Met Ile 385 390 395 400 Ser Glu Leu Ile Phe Asp Tyr Leu Pro Gly His Arg Cys Gln Asn Glu 405 410 415 Ile Cys Arg Val Lys Leu Lys Lys Leu Leu Gln Pro Tyr Thr Ser Thr 420 425 430 Leu Phe Phe Cys Ala Tyr Asn Asn Thr Arg Lys His Pro Asn Gly Leu 435 440 445 Pro Ala Arg Arg Ser Pro Glu Arg Arg Ala Pro Asp Ala Thr Pro Asn 450 455 460 Ile Pro Arg Leu Ala Tyr Arg Arg Ser Ala Thr Thr Ser Pro Glu Val 465 470 475 480 Glu Pro Ala Pro Pro Ser Arg Met Thr Ser Ser Ser Pro Arg Val Asp 485 490 495 Ser Arg Gly Gly Gly Gly Asp Arg Arg Gly Asp Ser Ser Ser Thr Ser 500 505 510 Ser Asn His His Arg His His Thr Arg Arg Ala Arg Thr Arg Ser Thr 515 520 525 His Asp Ser Ser Ser Ser Gly Ser Arg Arg Arg Ser Ser Ala Thr Asp 530 535 540 Gly Arg Arg Ser Arg Arg Gly Ser Arg Arg Gly Glu Ala Gln Arg Glu 545 550 555 560 Ser Asn Gly His His Ser Ser Lys Ser Pro Ser Thr Val Ser Ser Thr 565 570 575 Thr Val His Gly Gln Asn Gly Ala Arg Gly Asp Ser Ala Pro Ser Arg 580 585 590 Lys Ser Gln Gln Ser Gln Gln Gln Pro Glu Thr Thr Ser Lys Glu Ser 595 600 605 Ser Lys Thr Ala Ala Met Pro Pro Pro Pro Ser Pro Cys Ser Pro Ser 610 615 620 Pro Ala Ser Arg Glu Arg Arg Pro Ser Lys Ser Pro Ser Ser Ser Pro 625 630 635 640 Arg Pro His Asp Pro Pro Ser Gly Glu Pro Ala Asp Ala Glu Lys Glu 645 650 655 Leu Ala Thr Ala Gly Asp Glu Asp Glu Gly Val Arg Ser Pro Gly Glu 660 665 670 Cys Ser Val Ala Thr Arg Arg Gly Ser Ser Ala Asp Glu Ser Ser Asp 675 680 685 Ser Ser Ser Ser Ser Ser Asp Ser Ser Ser Ser Ser Asp Glu Glu Glu 690 695 700 Ser Asp Val Glu Asp Cys Arg Glu Leu Asp Leu Gln Ser Lys Arg Leu 705 710 715 720 Glu Glu Ala Leu Glu Glu Arg Cys Glu Arg Asp Phe Glu Ala Asp Asp 725 730 735 Glu Glu Phe Ala Glu Pro Ile Glu Glu Asp Asp Leu His Cys Ser Leu 740 745 750 Asp Met Glu Glu Asp Ile Glu Asp Glu Pro Leu Asp Pro Glu Thr Glu 755 760 765 Ser Val Trp Thr Ala Ser Val Thr Pro Leu Ala Ala Pro Pro Ser Ile 770 775 780 Arg Ile Leu Asp His Glu Pro Gly Asp Ala Glu Glu Glu Glu Glu Ser 785 790 795 800 Asp Thr Asp Phe Tyr Asp Glu Thr Asp Gln Pro Leu Asn Lys Arg Ile 805 810 815 His Leu Arg Ser Ala Thr Pro Thr Asp Asp Val Ile Met Glu Cys Asp 820 825 830 Leu Ser Tyr Ser Glu Met Asp Ser Asp 835 840 12 744 PRT Human cytomegalovirus 12 Met Glu Leu His Ser Arg Gly Arg His Asp Ala Pro Ser Leu Ser Ser 1 5 10 15 Leu Ser Glu Arg Glu Arg Arg Ala Arg Arg Ala Arg Arg Phe Cys Leu 20 25 30 Asp Tyr Glu Pro Val Pro Arg Lys Phe Arg Arg Glu Arg Ser Pro Thr 35 40 45 Ser Pro Ser Thr Arg Asn Gly Ala Ala Ala Ser Glu His His Leu Ala 50 55 60 Glu Asp Thr Val Gly Ala Ala Ser His His His Arg Pro Cys Val Pro 65 70 75 80 Ala Arg Arg Pro Arg Tyr Ser Lys Asp Asp Asp Thr Glu Gly Asp Pro 85 90 95 Asp His Tyr Pro Pro Pro Leu Pro Pro Ser Ser Arg His Ala Leu Gly 100 105 110 Gly Thr Gly Gly His Ile Ile Met Gly Thr Ala Gly Phe Arg Gly Gly 115 120 125 His Arg Ala Ser Ser Ser Phe Lys Arg Arg Val Ala Ala Ser Ala Ser 130 135 140 Val Pro Leu Asn Pro His Tyr Gly Lys Ser Tyr Asp Asn Asp Asp Gly 145 150 155 160 Glu Pro His His His Gly Gly Asp Ser Thr His Leu Arg Arg Arg Val 165 170 175 Pro Ser Cys Pro Thr Thr Phe Gly Ser Ser His Pro Ser Ser Ala Asn 180 185 190 Asn His His Gly Ser Ser Ala Gly Pro Gln Gln Gln Gln Met Leu Ala 195 200 205 Leu Ile Asp Asp Glu Leu Asp Ala Met Asp Glu Asp Glu Leu Gln Gln 210 215 220 Leu Ser Arg Leu Ile Glu Lys Lys Lys Arg Ala Arg Leu Gln Arg Gly 225 230 235 240 Ala Ala Ser Ser Gly Thr Ser Pro Ser Ser Thr Ser Pro Val Tyr Asp 245 250 255 Leu Gln Arg Tyr Thr Ala Glu Ser Leu Arg Leu Ala Pro Tyr Pro Ala 260 265 270 Asp Leu Lys Val Pro Thr Ala Phe Pro Gln Asp His Gln Pro Arg Gly 275 280 285 Arg Ile Leu Leu Ser His Asp Glu Leu Met His Thr Asp Tyr Leu Leu 290 295 300 His Ile Arg Gln Gln Phe Asp Trp Leu Glu Glu Pro Leu Leu Arg Lys 305 310 315 320 Leu Val Val Glu Lys Ile Phe Ala Val Tyr Asn Ala Pro Asn Leu His 325 330 335 Thr Leu Leu Ala Ile Ile Asp Glu Thr Leu Ser Tyr Met Lys Tyr His 340 345 350 His Leu His Gly Leu Pro Val Asn Pro His Asp Pro Tyr Leu Glu Thr 355 360 365 Val Gly Gly Met Arg Gln Leu Leu Phe Asn Lys Leu Asn Asn Leu Asp 370 375 380 Leu Gly Cys Ile Leu Asp His Gln Asp Gly Trp Gly Asp His Cys Ser 385 390 395 400 Thr Leu Lys Arg Leu Val Lys Lys Pro Gly Gln Met Ser Ala Trp Leu 405 410 415 Arg Asp Asp Val Cys Asp Leu Gln Lys Arg Pro Pro Glu Thr Phe Ser 420 425 430 Gln Pro Met His Arg Ala Met Ala Tyr Val Cys Ser Phe Ser Arg Val 435 440 445 Ala Val Ser Leu Arg Arg Arg Ala Leu Gln Val Thr Gly Thr Pro Gln 450 455 460 Phe Phe Asp Gln Phe Asp Thr Asn Asn Ala Met Gly Thr Tyr Arg Cys 465 470 475 480 Gly Ala Val Ser Asp Leu Ile Leu Gly Ala Leu Gln Cys His Glu Cys 485 490 495 Gln Asn Glu Met Cys Glu Leu Arg Ile Gln Arg Ala Leu Ala Pro Tyr 500 505 510 Arg Phe Met Ile Ala Tyr Cys Pro Phe Asp Glu Gln Ser Leu Leu Asp 515 520 525 Leu Thr Val Phe Ala Gly Thr Thr Thr Thr Thr Ala Ser Asn His Ala 530 535 540 Thr Ala Gly Gly Gln Gln Arg Gly Gly Asp Gln Ile His Pro Thr Asp 545 550 555 560 Glu Gln Tyr Ala Asn Met Glu Ser Arg Thr Asp Pro Ala Thr Leu Thr 565 570 575 Ala Tyr Asp Lys Lys Asp Arg Glu Gly Ser His Arg His Pro Ser Pro 580 585 590 Met Ile Ala Ala Ala Pro Pro Ala Gln Pro Pro Ser Gln Pro Gln Gln 595 600 605 His Tyr Ser Glu Gly Glu Leu Glu Glu Asp Glu Asp Ser Asp Asp Ala 610 615 620 Ser Ser Gln Asp Leu Val Arg Ala Thr Asp Arg His Gly Asp Thr Val 625 630 635 640 Val Tyr Lys Thr Thr Ala Val Pro Pro Ser Pro Pro Ala Pro Leu Ala 645 650 655 Gly Val Arg Ser His Arg Gly Glu Leu Asn Leu Met Thr Pro Ser Pro 660 665 670 Ser His Gly Gly Ser Pro Pro Gln Val Pro His Lys Gln Pro Ile Ile 675 680 685 Pro Val Gln Ser Ala Asn Gly Asn His Ser Thr Thr Ala Thr Gln Gln 690 695 700 Gln Gln Pro Pro Pro Pro Pro Pro Pro Pro Pro Val Pro Gln Glu Asp 705 710 715 720 Asp Ser Val Val Met Arg Cys Gln Thr Pro Asp Tyr Glu Asp Met Leu 725 730 735 Cys Tyr Ser Asp Asp Met Asp Asp 740 13 455 PRT human herpesvirus 8 13 Met Val Gln Ala Met Ile Asp Met Asp Ile Met Lys Gly Ile Leu Glu 1 5 10 15 Asp Ser Val Ser Ser Ser Glu Phe Asp Glu Ser Arg Asp Asp Glu Thr 20 25 30 Asp Ala Pro Thr Leu Glu Asp Glu Gln Leu Ser Glu Pro Ala Glu Pro 35 40 45 Pro Ala Asp Glu Arg Ile Arg Gly Thr Gln Ser Ala Gln Gly Ile Pro 50 55 60 Pro Pro Leu Gly Arg Ile Pro Lys Lys Ser Gln Gly Arg Ser Gln Leu 65 70 75 80 Arg Ser Glu Ile Gln Phe Cys Ser Pro Leu Ser Arg Pro Arg Ser Pro 85 90 95 Ser Pro Val Asn Arg Tyr Gly Lys Lys Ile Lys Phe Gly Thr Ala Gly 100 105 110 Gln Asn Thr Arg Pro Pro Pro Glu Lys Arg Pro Arg Arg Arg Pro Arg 115 120 125 Asp Arg Leu Gln Tyr Gly Arg Thr Thr Arg Gly Gly Gln Cys Arg Ala 130 135 140 Ala Pro Lys Arg Ala Thr Arg Arg Pro Gln Val Asn Cys Gln Arg Gln 145 150 155 160 Asp Asp Asp Val Arg Gln Gly Val Ser Asp Ala Val Lys Lys Leu Arg 165 170 175 Leu Pro Ala Ser Met Ile Ile Asp Gly Glu Ser Pro Arg Phe Asp Asp 180 185 190 Ser Ile Ile Pro Arg His His Gly Ala Cys Phe Asn Val Phe Ile Pro 195 200 205 Ala Pro Pro Ser His Val Pro Glu Val Phe Thr Asp Arg Asp Ile Thr 210 215 220 Ala Leu Ile Arg Ala Gly Gly Lys Asp Asp Glu Leu Ile Asn Lys Lys 225 230 235 240 Ile Ser Ala Lys Lys Ile Asp His Leu His Arg Gln Met Leu Ser Phe 245 250 255 Val Thr Ser Arg His Asn Gln Ala Tyr Trp Val Ser Cys Arg Arg Glu 260 265 270 Thr Ala Ala Ala Gly Gly Leu Gln Thr Leu Gly Ala Phe Val Glu Glu 275 280 285 Gln Met Thr Trp Ala Gln Thr Val Val Arg His Gly Gly Trp Phe Asp 290 295 300 Glu Lys Asp Ile Asp Ile Ile Leu Asp Thr Ala Ile Phe Val Cys Asn 305 310 315 320 Ala Phe Val Thr Arg Phe Arg Leu Leu His Leu Ser Cys Val Phe Asp 325 330 335 Lys Gln Ser Glu Leu Ala Leu Ile Lys Gln Val Ala Tyr Leu Val Ala 340 345 350 Met Gly Asn Arg Leu Val Glu Ala Cys Asn Leu Leu Gly Glu Val Lys 355 360 365 Leu Asn Phe Arg Gly Gly Leu Leu Leu Ala Phe Val Leu Thr Ile Pro 370 375 380 Gly Met Gln Ser Arg Arg Ser Ile Ser Ala Arg Gly Gln Glu Leu Phe 385 390 395 400 Arg Thr Leu Leu Glu Tyr Tyr Arg Pro Gly Asp Val Met Gly Leu Leu 405 410 415 Asn Val Ile Val Met Glu His His Ser Leu Cys Arg Asn Ser Glu Cys 420 425 430 Ala Ala Ala Thr Arg Ala Ala Met Gly Ser Ala Lys Phe Asn Lys Gly 435 440 445 Leu Phe Phe Tyr Pro Leu Ser 450 455 14 426 PRT Herpesvirus saimiri 14 Met Ala Gln Ala Met Val Thr Asn Cys Gln Met Glu Asp Ile Ile Glu 1 5 10 15 Gly Ile Ser Ser Asp Asp Asp Phe Asp Ser Ser Asp Ser Ser Ser Asp 20 25 30 Glu Glu Glu Ser Asp Thr Ser Pro Gln Ile Met Lys Ser Asp Val Thr 35 40 45 Met Ala Ser Pro Pro Ser Thr Pro Glu Pro Ser Pro Asp Val Ser Ala 50 55 60 Ser Thr Ser Asn Leu Lys Arg Glu Arg Gln Arg Ser Pro Ile Thr Trp 65 70 75 80 Glu His Gln Ser Pro Leu Ser Arg Val Tyr Arg Ser Pro Ser Pro Met 85 90 95 Arg Phe Gly Lys Arg Pro Arg Ile Ser Ser Asn Ser Thr Ser Arg Ser 100 105 110 Cys Lys Thr Ser Trp Ala Asp Arg Val Arg Glu Ala Ala Ala Gln Arg 115 120 125 Arg Pro Ser Arg Pro Phe Arg Lys Pro Tyr Ser His Pro Arg Asn Gly 130 135 140 Pro Leu Arg Asn Gly Pro Pro Arg Ala Pro Pro Leu Leu Lys Leu Phe 145 150 155 160 Asp Ile Ser Ile Leu Pro Lys Ser Gly Glu Pro Lys Leu Phe Leu Pro 165 170 175 Val Pro Ser Leu Pro Cys Gln Glu Ala Glu Lys Thr Asn Asp Lys Tyr 180 185 190 Val Leu Ala Met Ala Gln Arg Ala Met His Asp Val Pro Ile Ser Ser 195 200 205 Lys Gln Leu Thr Ala Asn Leu Leu Pro Val Lys Phe Lys Pro Leu Leu 210 215 220 Ser Ile Val Arg Tyr Thr Pro Asn Tyr Tyr Tyr Trp Val Ser Met Arg 225 230 235 240 Lys Glu Thr Ile Ala Ser Ala Asn Leu Cys Thr Val Ala Ala Phe Leu 245 250 255 Asp Glu Ser Leu Cys Trp Gly Gln Gln Tyr Leu Lys Asn Asp Phe Ile 260 265 270 Phe Ser Glu Asn Gly Lys Asp Ile Ile Leu Asp Thr Ser Ser Ala Leu 275 280 285 Leu Ser Gln Leu Val His Lys Ile Lys Met Leu Pro Phe Cys His Cys 290 295 300 Leu Met Gln Thr Thr Pro Gln Asp His Ile Val Lys Gln Val Cys Tyr 305 310 315 320 Leu Ile Ala Ser Asn Asn Arg Ile Leu Asp Ala Val Arg Tyr Leu Gln 325 330 335 Thr Ser Val Ile Lys Ser Pro Ile Val Leu Leu Leu Ala Tyr Ala Val 340 345 350 Cys Leu Pro Ala Ala Ile Ile Cys Thr Lys Asn Glu Thr Gln Leu Tyr 355 360 365 Ser His Cys Met Arg Ile Leu Lys Glu Tyr Arg Pro Gly Asp Val Met 370 375 380 Asn Ile Leu His Glu Ser Leu Thr Gln His Leu Asn Lys Cys Pro Ser 385 390 395 400 Ser Thr Cys Ala Tyr Thr Thr Arg Ala Ile Val Gly Thr Lys Ala Asn 405 410 415 Thr Thr Gly Leu Phe Phe Leu Pro Thr Gln 420 425 15 428 PRT Bovine herpesvirus 4 15 Met Ala Gln Ala Met Leu Thr Met Asp Cys Met Arg Glu Ile Ile Glu 1 5 10 15 Asp Leu Ser Ser Asp Ile Asp Ser Phe Ser Gly Gly Glu Ser Ile Asp 20 25 30 Met Glu Ser Glu Leu Glu Glu Gly Glu Ile Glu Ser Asp Thr Asn Ser 35 40 45 Ser Lys Pro Pro Pro Pro Gln Asp Leu Ser Lys Pro Pro Met Met Arg 50 55 60 Ile Pro Arg Lys Arg Val Ala Ser Pro Asp Asn Glu Arg Met Glu Tyr 65 70 75 80 Arg Ser Pro Leu Asn Arg Thr Tyr Pro Pro Pro Phe Thr Glu Arg Tyr 85 90 95 Gly Lys Arg Arg Arg Leu Thr Ala Gly Arg Pro Asn Trp Ser Gly Arg 100 105 110 Val Asn Glu Asp Lys Gly Arg Tyr Arg Arg Arg Gly Leu Ser Asp Asn 115 120 125 Lys Thr Ile Arg His Thr Gln Ala Ser Ile Lys Asp Glu Val Ala Val 130 135 140 Ser Leu Arg Lys Met Lys Ile Pro Thr Gly Met Ile Arg Arg Ala Gly 145 150 155 160 Glu Lys Pro Phe Asp Glu Thr Leu Leu Ser Ser Gly Gly Pro Gly Arg 165 170 175 Tyr Ser Val Phe Leu Pro Arg Ala Pro Glu Phe Lys Leu Glu Arg Tyr 180 185 190 Thr Asp Lys Leu Val Ser Ser Leu Val Glu Lys Gly Gly Glu Asn Gly 195 200 205 Ala Gly Ile Ser Lys Lys Leu Ser His Leu Lys Leu Ser Ser Asn Phe 210 215 220 Ser Val Ile His Ser Phe Leu Asn Lys Ser Ile Asn Tyr His Tyr Trp 225 230 235 240 Val Cys Leu Arg Lys Glu Thr Met Gly Ser Cys Gly Leu Thr Ser Leu 245 250 255 Met Leu Phe Leu Glu Glu Thr Cys Cys Trp Ala Gln Leu Cys Thr Ser 260 265 270 Asn Asp Val Ser Ile Asn Gly Phe Ser Asn Asp Ile Ile Leu Asn Ser 275 280 285 Ala Asn Phe Leu Ser Val Gln Ile Met Phe Lys Leu Arg Ser Leu Val 290 295 300 Met Pro Cys Phe Ala Arg Glu Ala His Asn Ile Ser Leu Val Lys Gln 305 310 315 320 Leu Gly Tyr Leu Val Ser Thr Thr Asn Lys Ile Gln Thr Ala Ala Ser 325 330 335 Leu Ile Arg Glu Leu Lys Leu Asp Thr Lys Leu Cys Leu Leu Ala Ala 340 345 350 Phe Ala Ile Val Val Pro Thr Leu Leu Glu Thr Asp Lys Thr Glu His 355 360 365 Gly Thr Tyr Ala Phe Phe Met Gln Tyr Ile Asn Arg Tyr Arg Pro Gly 370 375 380 Cys Ile Met Ser Leu Tyr Asn Asp Val Ile Ser Ser His Ser Arg Glu 385 390 395 400 Cys Thr Ser Arg Leu Cys Ile Ala Asn Thr Arg Ala Leu Ala Gly Thr 405 410 415 Lys Asp Lys Thr Lys Gly Leu Phe Phe Cys Pro Ile 420 425 16 436 PRT Avian herpesvirus 1 16 Met Ala Gln Gln Ala Ile Val Thr Met Ser Ala Leu Arg Arg Thr Met 1 5 10 15 Glu Val Ser Asp Ser Gly Asp Val Ser Ile Asp Ile Ser Ala Glu Asp 20 25 30 Ser Asn Asp Ser Phe His Leu Glu Glu Ser Val Asp Asp Cys Met Asp 35 40 45 Asp Cys Lys Pro Asn Asn Arg Pro Asn Pro Ile Ser Met Lys Pro Ala 50 55 60 Lys Arg Arg Val Phe Met Val Pro Lys Arg Glu Arg Ser Lys Thr Pro 65 70 75 80 Val Gln His Thr Ser Pro Leu Asn Arg Leu Tyr Pro Asn Val Val Leu 85 90 95 Gly Lys Gln His Gly Tyr Lys Gln Arg Pro Ala Pro Ser Ala Arg Ser 100 105 110 Arg Arg Pro Gln Pro Tyr Ser Ala Arg Lys Asp Ser Ala Ala Lys Pro 115 120 125 Gln Ser Thr Pro Ser Asn Gln Asn Pro Leu Thr Glu Leu Leu Lys Asn 130 135 140 Val Asp Pro Ala Ile Ala Ser Arg Ile Thr Glu Met Arg Ile Pro Arg 145 150 155 160 Ser Met Leu Arg Thr Pro Ser Gly Gln Pro Phe Ala His Trp Leu Met 165 170 175 Pro Ser Ala Glu Asp Ser Ser Lys Phe Ile Asn Val Asn Pro Val Asn 180 185 190 Met Glu Val Glu Glu His Val Asn Val Val Val Arg Arg Cys Thr Glu 195 200 205 Trp Ala Leu Ile Ser Ser Arg Leu Gln Asp Lys Ser Ile Ser Thr Lys 210 215 220 Tyr Leu Ala Glu Asn Phe Tyr Asp Leu Arg Asp Phe Ala Gln Arg Ser 225 230 235 240 Ile Asn Lys Ser Ala Trp Ile Asn Leu Arg Arg Glu Ala Ile Ala Asn 245 250 255 Ala Gly Phe Val Asn Leu Cys Ala Phe Ala Asp Glu Met Met Met Trp 260 265 270 Leu Gln Leu Asn Leu Asn Asn Gln Gly Ser Trp Lys Ala Cys Arg Glu 275 280 285 Asp Ile Ile Leu Thr Gly Ala Pro Asp Met Cys Phe His Ala Leu Gln 290 295 300 Lys Val Arg Ala Phe Ile Lys Cys Phe Leu Arg Glu Arg His Gln Arg 305 310 315 320 Ala Leu Val Asn Ala Leu Cys His Ile Ile Cys Phe Glu Gly Gly Ile 325 330 335 Lys Gln Ala Ala Thr Leu Cys Gln Glu Leu Phe Phe Asp Phe Lys Val 340 345 350 Gly Leu Met Val Leu Tyr Phe Leu Thr Pro Tyr Ala Phe Leu Tyr Ser 355 360 365 His Thr Ile Pro Gln Cys Asn Phe Gly Gly Tyr Phe Ser Lys Cys Val 370 375 380 Ala Gln Tyr Thr Pro Gly Ala Val Thr Gly Leu Leu Asn Ser Ala Ile 385 390 395 400 Glu Asp His Tyr Lys Asp Cys Thr Ser Gln Asp Cys Thr Asn Leu Ile 405 410 415 Thr Ala Ile Val Ser Pro Glu Thr Ser Asn Lys Gly Leu Leu Phe Phe 420 425 430 Pro Leu Pro Met 435 17 409 PRT Murineherpesvirus68 17 Met Ala Gln Gln Met Leu Glu Ala Gly Ala Leu Asp Gln Met Met Glu 1 5 10 15 Gly Leu Pro Ser Asp Phe Asp Phe Asp Thr Ser Asp Glu Glu Gly Glu 20 25 30 Leu Ser Asp Ser Pro Pro Val Glu Glu Pro Thr Gly Pro Val Arg Asp 35 40 45 Val Val Tyr Glu Pro Asp Pro Leu Phe Asp Asp Pro Pro Pro Thr Pro 50 55 60 Ser Pro Asp Val Lys Pro Pro Ser Pro Lys Ala Arg Lys Arg Ala Leu 65 70 75 80 Ser Pro Glu Ile Val His Asn Ser Pro Leu Leu Arg Asp Thr Thr Lys 85 90 95 Tyr Glu Pro Ala Pro Lys Arg Ser Tyr Ser Tyr His Pro Arg Arg Ser 100 105 110 Pro Gln Arg Glu Asn Ala Asn Gln Lys Gln Lys Arg Gly Pro Asp Ser 115 120 125 Arg Arg Pro Asn Arg Trp Asn Gln Lys Ser Gln Lys Gln Tyr Trp Ser 130 135 140 Pro Lys Pro Leu Leu Asp Tyr Ser Lys Ile Pro Arg Ala Glu Tyr Lys 145 150 155 160 Asn Ala Lys Leu Leu Val Pro Thr Thr Gly Lys Leu Arg Pro Glu Phe 165 170 175 Tyr Thr Asp Arg Phe Val Asp Ala Ile Ile Gln Asn Ala Ala Arg Asn 180 185 190 Cys Pro Val Ser Glu Lys Ala Val Ser Leu Lys Asn Ile Glu Glu Ser 195 200 205 Phe Lys Leu Leu Asn Ser Phe Phe Asn Ser Gly Ile Asn Lys Asp His 210 215 220 Trp Leu Ser Thr Arg Tyr Phe Ala Ile Phe Asn Asn Gly Leu Val Val 225 230 235 240 Leu Thr His Met Leu Asp Glu Gln Leu Ala Trp Ala Tyr Ala Cys Leu 245 250 255 Lys His Gly Arg Glu Leu Pro Thr Asp Asp Ile Leu Met Ser Thr Ser 260 265 270 Glu Lys Leu Ser Gln Gln Leu Val Ile Lys Leu Ile Glu Val Ile Lys 275 280 285 Cys Ile Glu Lys Asp Gly Ile Phe Ser Arg Ile Leu Lys Gly Val Ala 290 295 300 Asp Ala Val Cys Leu Lys Ala Gln Phe Leu Arg Gly Met Ile Thr Leu 305 310 315 320 Lys Arg Thr Pro Cys Ser Leu Pro Met Tyr Thr Leu Phe Val Tyr Val 325 330 335 Leu Thr Ile Pro Thr Leu Arg Thr Arg Val Ile Arg Asp Pro Leu Leu 340 345 350 Thr Gln Cys Lys Asp Val Val Leu Lys Tyr Gln Pro Gly Asp Cys Ile 355 360 365 Thr Leu Leu Lys Ala Ala Leu Asn Cys His Gln Cys Asn Lys Asp Cys 370 375 380 Asp Lys Cys Lys Tyr Ile Leu Asp Pro Leu Leu Gly Gln Thr His Arg 385 390 395 400 Thr Lys Gly Val Phe Phe Val Cys Glu 405 18 479 PRT Epstein-Barr virus 18 Met Val Pro Ser Gln Arg Leu Ser Arg Thr Ser Ser Ile Ser Ser Asn 1 5 10 15 Glu Asp Pro Ala Glu Ser His Ile Leu Glu Leu Glu Ala Val Ser Asp 20 25 30 Thr Asn Thr Asp Cys Asp Leu Asp Pro Met Glu Gly Ser Glu Glu His 35 40 45 Ser Thr Asp Gly Glu Ile Ser Ser Ser Glu Glu Glu Asp Glu Asp Pro 50 55 60 Thr Pro Ala His Ala Ile Pro Ala Arg Pro Ser Ser Val Val Ile Thr 65 70 75 80 Pro Thr Ser Ala Ser Phe Val Ile Pro Arg Lys Lys Trp Asp Leu Gln 85 90 95 Asp Lys Thr Val Thr Leu His Arg Ser Pro Leu Cys Arg Asp Glu Asp 100 105 110 Glu Lys Glu Glu Thr Gly Asn Ser Ser Tyr Thr Arg Gly His Lys Arg 115 120 125 Arg Arg Gly Glu Val His Gly Cys Thr Asp Glu Ser Tyr Gly Lys Arg 130 135 140 Arg His Leu Pro Pro Gly Ala Arg Ala Pro Arg Ala Pro Arg Ala Pro 145 150 155 160 Arg Val Pro Arg Ala Pro Arg Ser Pro Arg Ala Pro Arg Ser Asn Arg 165 170 175 Ala Thr Arg Gly Pro Arg Ser Glu Ser Arg Gly Ala Gly Arg Ser Thr 180 185 190 Arg Lys Gln Ala Arg Gln Glu Arg Ser Gln Arg Pro Leu Pro Asn Lys 195 200 205 Pro Trp Phe Asp Met Ser Leu Val Lys Pro Val Ser Lys Ile Thr Phe 210 215 220 Val Thr Leu Pro Ser Pro Leu Ala Ser Leu Thr Leu Glu Pro Ile Gln 225 230 235 240 Asp Pro Phe Leu Gln Ser Met Leu Ala Val Ala Ala His Pro Glu Ile 245 250 255 Gly Ala Trp Gln Lys Val Gln Pro Arg His Glu Leu Arg Arg Ser Tyr 260 265 270 Lys Thr Leu Arg Glu Phe Phe Thr Lys Ser Thr Asn Lys Asp Thr Trp 275 280 285 Leu Asp Ala Arg Met Gln Ala Ile Gln Asn Ala Gly Leu Cys Thr Leu 290 295 300 Val Ala Met Leu Glu Glu Thr Ile Phe Trp Leu Gln Glu Ile Thr Tyr 305 310 315 320 His Gly Asp Leu Pro Leu Ala Pro Ala Glu Asp Ile Leu Leu Ala Cys 325 330 335 Ala Met Ser Leu Ser Lys Val Ile Leu Thr Lys Leu Lys Glu Leu Ala 340 345 350 Pro Cys Phe Leu Pro Asn Thr Arg Asp Tyr Asn Phe Val Lys Gln Leu 355 360 365 Phe Tyr Ile Thr Cys Ala Thr Ala Arg Gln Asn Lys Val Val Glu Thr 370 375 380 Leu Ser Ser Ser Tyr Val Lys Gln Pro Leu Cys Leu Leu Ala Ala Tyr 385 390 395 400 Ala Ala Val Ala Pro Ala Tyr Ile Asn Ala Asn Cys Arg Arg Arg His 405 410 415 Asp Glu Val Glu Phe Leu Gly His Tyr Ile Lys Asn Tyr Asn Pro Gly 420 425 430 Thr Leu Ser Ser Leu Leu Thr Glu Ala Val Glu Thr His Thr Arg Asp 435 440 445 Cys Arg Ser Ala Ser Cys Ser Arg Leu Val Arg Ala Ile Leu Ser Pro 450 455 460 Gly Thr Gly Ser Leu Gly Leu Phe Phe Val Pro Gly Leu Asn Gln 465 470 475

Classifications
U.S. Classification435/6.16, 424/229.1, 514/151, 514/618, 424/204.1, 435/5
International ClassificationA61K38/00, C07K14/035, A61P31/22, G01N33/569
Cooperative ClassificationC07K14/005, C12N2710/16622, A61K38/00, G01N2500/00, G01N33/56994
European ClassificationC07K14/005, G01N33/569K4
Legal Events
DateCodeEventDescription
Nov 10, 2009FPExpired due to failure to pay maintenance fee
Effective date: 20090920
Sep 20, 2009LAPSLapse for failure to pay maintenance fees
Mar 30, 2009REMIMaintenance fee reminder mailed
Feb 11, 2003ASAssignment
Owner name: UNIVERSITY COURT OF THE UNIVERSITY OF GLASGOW, UNI
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MACLEAN, ALASDAIR RODERICK;REEL/FRAME:014169/0845
Effective date: 20030117
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CLEMENTS, JOHN BARKLIE;REEL/FRAME:014169/0836